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Genetic epidemiology of BRCA1 mutations in Norway
Abstract
Familial breast-ovarian cancer has been demonstrated to be frequent but unevenly distributed in Norway. This was assumed to be caused by the reduced population size created by the medieval Bubonic plagues 25 generations ago, and by the following rapid expansion. We have previously reported that four mutations account for 68% of the BRCA1 mutation carriers. Subsequent analysis has resulted in a total of 100 separate families carrying one of these founder mutations. The four mutations occurred on one specific BRCA1 haplotype each. The 1675delA, 816delGT and 3347delAG families originated from the South-West coast of Norway with a few families in the north, while the traceable ancestors of the 1135insA families clustered along the historical inland road from the South-East to mid-Norway. The carriers of each of the four mutations today are descendants of one or a few individuals surviving the plagues. We may identify the majority of BRCA1 mutation carriers in Norway by screening for local founder mutations.
... Further, isolation and reduction of gene flow within a geographical area can also manifest an increase in recessive Mendelian disorders [8,9] and founder variants. Indeed, geographically clustered and expanding BRCA1 founder variants have been previously reported for Norway [10,11]. ...
... It includes information about family structure and place of residence as postcodes, which were converted into longitude and latitude coordinates [22]. The biobank consists of families, as well as unrelated individuals, with partial pedigree information covering more than 50,000 individuals [10,11]. Its clinical aim was to provide benefit to patients from the established follow-up examinations aiming at early diagnosis and treatment. ...
... Further, the counties of Rogaland and Vest-Agder display elevated levels of within-county haplotype sharing (~13-14 cM), suggesting isolation and inbreeding (Fig. 2), as well as increased homozygosity (Fig. 3) and small N e (Table 1). This is in line with previous reports on genetic differentiation in southern Norway [10,11]. In this study, we have used place of residence as the geographical origin of samples, and not a place of birth, as that information was not available to us. ...
The aim of the present study was to describe the genetic structure of the Norwegian population using genotypes from 6369 unrelated individuals with detailed information about places of residence. Using standard single marker- and haplotype-based approaches, we report evidence of two regions with distinctive patterns of genetic variation, one in the far northeast, and another in the south of Norway, as indicated by fixation indices, haplotype sharing, homozygosity, and effective population size. We detect and quantify a component of Uralic Sami ancestry that is enriched in the North. On a finer scale, we find that rates of migration have been affected by topography like mountain ridges. In the broader Scandinavian context, we detect elevated relatedness between the mid- and northern border areas towards Sweden. The main finding of this study is that despite Norway’s long maritime history and as a former Danish territory, the region closest to mainland Europe in the south appears to have been an isolated region in Norway, highlighting the open sea as a barrier to gene flow into Norway.
... Founder mutations in BRCA1 and 2 have been described in many populations, i.e. the Ashkenazi-Jewish, Polish, Norwegian, and Icelandic [12][13][14]. Therefore, founder mutation testing in patients with relevant ancestry and family history has been a cost-efficient approach during the years with limited access to sequence analysis. ...
... One of the first studies carried out on BRCA epidemiology in Norway by , showed that 68% of the mutation carriers had one of the four most frequent Norwegian founder mutations in BRCA1 [16], c.1016dup, c.1556del, c.3328_3229del, c.697_698del, all demonstrated to be true founder mutations through haplotyping [13]. The variant c.1016dup was shown to originate in the south-eastern part of the country, while the other three originated from the south-western part of the country, before the Bubonic plague. ...
... From around 1995 and onwards, the laboratories performing BRCA analysis used various techniques. Initially, by using techniques such as denaturing gradient gel electrophoresis and sequencing methods, four recurrent BRCA1 mutations were identified in Norwegian families (c.1556del, c.3328_3229del, c.697_698del and c.1016dup) [13]. Eventually other cost-efficient/affordable tests, such as multiplex PCR fragment analysis and sequencing of shorter fragments were used to screen larger groups of individuals, as well as to detect mutations already found in the family. ...
Background:
Founder mutations in the two breast cancer genes, BRCA1 and BRCA2, have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian BRCA1 founder mutations were defined by haplotyping in 2001, and accounted for 68% of BRCA1 mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both BRCA1 and BRCA2 in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the BRCA1/2 carrier population of the largest clinic of hereditary cancer in Norway.
Methods:
A total of 2430 BRCA1 carriers from 669 different families, and 1092 BRCA2 carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations.
Results:
There were 120 different BRCA1 and 87 different BRCA2 variants among the mutation carriers. Forty-six per cent of the registered BRCA1/2 families (454/981) had a previously reported Norwegian founder mutation. The majority of BRCA1/2 mutations (71%) were rare, each found in only one or two families. Fifteen per cent of BRCA1 families and 25% of BRCA2 families had one of these rare variants. The four well-known Norwegian BRCA1 founder mutations previously confirmed through haplotyping were still the four most frequent mutations in BRCA1 carriers, but the proportion of BRCA1 mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.
Conclusions:
The spectrum of BRCA1 and BRCA2 mutations in the carrier population at Norway's largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives.
... Although not discussed above, the family histories of these cases are consistent with this mutation being highly penetrant for both breast and ovarian cancer. The family histories of the Norwegian families have been described previously [8]. ...
... Haplotype analysis was performed on selected cases from three families recruited from the Hereditary Cancer Clinic of McGill University in Montreal (2 Italian, 1 French Canadian), and three Dutch families from the Netherlands Cancer Institute (NKI) in Amsterdam. Haplotype analysis was previously done in Norway on six families [8]. The index patients were referred because of a personal and/or family history of breast or ovarian cancer and were subsequently found to be carriers of the BRCA1: 1135insA mutation. ...
... The BRCA1 mutation 1135insA (HGVS nomenclature: c.1135_1136insA) is a frameshift mutation occurring in exon 11. It has previously been identified as one of four founder mutations originating from the Eastern population of Norway [7,8]. In one series, approximately 1% of Norwegian women under the age of 70 years with ovarian cancer carried this mutation [9] and it accounts for ~20% of all BRCA1/2 mutation carriers demonstrated by DNA testing today in Norway (Møller, unpublished data). ...
Analysis of the chromosomal background upon which a mutation occurs can be used to reconstruct the origins of specific disease-causing mutations. The relatively common BRCA1 mutation, 1135insA, has been previously identified as a Norwegian founder mutation. We performed haplotype analysis of individuals from breast and ovarian cancer families from four different ethnic backgrounds who had been identified as carriers of the BRCA1: 1135insA mutation.
Four microsatellite markers (D17S855, D17S1322, D17S1323 and D17S1325) located within or near the BRCA1 gene were genotyped in mutation carriers from 6 families of French Canadian, Italian and Dutch descent. Haplotypes were inferred from the genotype data and compared between these families and with the previously reported Norwegian founder haplotype.
The 1135insA mutation was found to occur on three distinct haplotype backgrounds. The families from Norway shared a distinct haplotype while the families of French Canadian, Italian, and Dutch descent were found to occur on one of two additional, distinct backgrounds.
Our results indicate that while the Norwegian haplotype including 1135insA represents an ancient Norwegian mutation, the same mutation has occurred independently in the other populations examined. In centres where targeted mutation testing is performed, exclusively or prior to gene sequencing, our findings suggest that this recurring mutation should be included in targeted mutation panels, irrespective of the ethnic origin of the persons tested.
... The Norwegian cancer dataset (N = 5,151) was derived from a biobank of blood samples collected over a period of 25 years as a patient self-referral initiative for overrepresentation of cancer in families, with both clinical and research intent. The dataset consists of families, as well as unrelated individuals, with partial pedigree information covering more than 50,000 people 85,86 . Its clinical aim was to provide benefit to patients from the established follow-up examinations aiming at early diagnosis and treatment. ...
Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four genes associated with increased cancer risk; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer and CMTR2 for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; AURKB for any cancer, irrespective of site, and PPP1R15A for breast cancer, suggesting that inhibition of PPP1R15A may be a preventive strategy for breast cancer. Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis and cell stress response as a focus point for developing new therapeutics.
... Specific recurrent variants in BRCA1/2 genes have been delineated in certain populations, such as the Ashkenazi-Jewish, French-Canadian, Brazilian, Italian, Icelandic, and Polish populations [27][28][29][30]. For Turkey, several studies reported that the c.5329dup (also known as c.5266dup in alternate nomenclature) variant in BRCA1 is the most common detected variant, which is possibly attributed to a founder effect [31][32][33][34][35]. In our study, we also detected the c.5329dup variant in an EOBC patient with a positive family history. ...
Background
Early-onset breast cancer (EOBC) is a specific condition that affects women under the age of 45. BRCA pathogenic/likely pathogenic (P/LP) germline variants have been demonstrated to be harbored in a subgroup of EOBC individuals, and BRCA -positive genetic result offers an option to ensure more specified therapeutic implications. Establishing comprehensive BRCA1/2 genetic testing, including both the detection of small-scale mutations and large genomic rearrangements (LGRs), is needed for risk assessment and clinical management. In this study, we described a Turkish EOBC cohort along with their clinico-pathological characteristics and BRCA1/2 mutational profiles. A total of 67 unrelated patients were enrolled. Both next-generation sequencing (NGS)-based gene panel and multiplex ligation-dependent probe amplification (MLPA) were performed for BRCA1/2 variant identification. Patients' family medical history and hormone receptor status of the tumors were also recorded.
Results
14 (20.90%) patients were found to carry BRCA P/LP germline variants. (Nine were BRCA2 -positive, and five were BRCA1 -positive.) Two novel BRCA2 variants were detected. No significant differences were found between BRCA -positive vs. BRCA -negative or BRCA1 -positive vs. BRCA2 -positive for hormonal status and family history.
Conclusions
BRCA1/2 genes represent a predominant part of the genetic landscape of EOBC. Our results expand the spectrum of BRCA1/2 variants and provide knowledge of the BRCA1/2 variant prevalence in our cohort.
... In Italy, in the region of Tuscany, more than 73% of all detec ted mutations in the BRCA1 gene are the 3347delAG, 3404delA, 1499insA, and 5181del-GTT mutations [11]. More than 68% of all detected mutations in one of the regions of Nor-way are 1675delA, 3347delAG, 816delGT, and 1135insA mutations in the BRCA1 gene [12]. In this study and in previous studies, we have found that the most common mutation among BC patients in Ukraine is 5382insC in the BRCA1 gene, which is a progenitor, and other progenitor pathogenic variants are rarely detected. ...
Background. Currently, there is a great interest in the genetic testing of BRCA1 and BRCA2 due to the fact that for patients with breast cancer (BC) with pathogenic variants of these genes, the use of the PARP inhibitors could be also provided in addition to implemented treatment protocols. The aim of this study was to characterize the molecular genetic structure of the BRCA1 gene in BC patients without progenitor germline mutations taking into account the methylation state of the promoter region. Materials and Methods. The study involved 210 patients with newly diag-nosed BC. The most common germline pathogenic variants of the BRCA1 (185delAG, 5382insC, 4153delA, T300G) and BRCA2 (6174delT) genes were identified in the peripheral blood. A subgroup of 14 patients without progenitor pathological variants of the BRCA1 and BRCA2 genes and with a family history of cancer was randomly selected. For them, BRCA1 gene sequencing by Sanger and hypermethylation of the BRCA1 gene promoter region were analyzed. Results. The following frequencies of BRCA1 mutations were determined in the general group: 5382insC – 8.6%, 4153delA – 0.5%, T300G – 0.5%. The analysis of the BRCA1 gene by Sanger sequencing revealed 11 BRCA1 gene variants in 10 out of 14 BC patients. All of them, according to the currently available data, were defined as “benign” and not clinically relevant. The frequency of the detection of hypermethylation of the BRCA1 gene promoter region in the randomly selected group of patients was 14.3%. Conclusions. In BC patients, not only common mutations but also the methylation status of the BRCA1 gene promoter region in the peripheral blood should be determined. The whole-genome sequencing of the BRCA1 gene may be the last step in determining the genetic characteristics of BC patients carried out to optimize the treatment and improve survival thanks to the higher prevalence of the progenitor mutations and hypermethylation of the BRCA1 gene promoter.
... In addition, haplotype analysis of Maghrebian and central European carriers of the BRCA1mutation c.181T>G may reveal whether the origin of this mutation in Maghrebian populations is linked to the Vandals, an East Germanic tribe, who invaded and established a kingdom in North Africa during antiquity [56]. We captured another founder mutation, the c.1016dupABRCA1that has been described as one of four founder mutations originating from the Eastern population of Norway [57]. This mutation has been reported for the first time in a Moroccan cohort [19], and then in a recent study [21]. ...
Introduction: Breast cancer (BC) is a heterogeneous disease defined by the accumulation of various molecular alterations that accord each tumor a specific phenotype. Our study aimed to summarize all studies conducted on genetic alterations associated with BC in Moroccan women. Methods: We systematically searched literature databases from the time of inception until 31 August 2021 to collect information concerning the mutation spectrum for BC in Morocco. Results: We identified twenty-three studies including 1858 cases. According to our literature search, twenty-nine mutations were detected in 92/468 (19.66%) patients for BRCA1/BRCA2 genes. We captured eighteen mutations dispersed in the exons 2, 3, 5, 11, 16, 17, 18, and 20 of the BRCA1 gene (c.68_69delAG
... Some variants have been observed with high frequency in certain regions and races and are called founder mutations [4]. Founder mutations in BRCA1/2 have been reported in Ashkenazi Jewish [5][6][7][8] and European countries [9][10][11], while there are still few reports in Asian countries [12,13]. ...
Background: Some germline pathogenic variants (PVs) have been observed with high frequency in certain regions and races and are called founder mutations. Founder mutations in BRCA1/2 genes have rarely been reported in Japan. At Kakogawa Central City Hospital, BRCA2 c.5576_5579del accounted for approximately 70% of PVs detected by BRCA1/2 genetic testing. Therefore, we conducted a retrospective observational study to investigate its distribution in Hyogo Prefecture.
Patients and Methods: This study was conducted at Kobe University Hospital and three collaborating institutions. Breast cancer patients with germline PVs detected by BRCA1/2 genetic testing between July 1, 2018 and March 31, 2021 were included. The clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2c.5576_5579del and those of other PVs. The detection rate of BRCA2c.5576_5579del was also compared with that observed in a previous report.
Results: A total of 38 breast cancer patients were included; 14 of them underwent testing for companion diagnosis to poly ADP-ribose polymerase inhibitor treatment and 24 underwent testing for diagnosis of hereditary breast and ovarian cancer. PVs in BRCA1 andBRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2c.5576_5579del carriers. There were no clinicopathological differences between BRCA2PV carriers and BRCA2 c.5576_5579del carriers. BRCA2c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital.
Conclusion: Our study revealed a strong founder effect for BRCA2 c.5576_5579del in breast cancer patients in Hyogo Prefecture, especially in Kakogawa City. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization.
... These mutations have also been identified at lower frequencies in other populations and ethnic groups [13]. Similarly, other recurring variants have been reported in different populations including Europeans and Hispanics [10,[14][15][16][17]. However, unlike the AJ population, specific mutation prevalence is less clearly defined in other racial and ethnic groups. ...
Purpose
The prevalence of pathogenic variants in BRCA1 and BRCA2 in populations other than Ashkenazi Jewish (AJ) is not well defined. We describe the racial and ethnic-specific prevalence of BRCA1/2 pathogenic variants and variants of uncertain significance (VUS) among individuals referred for genetic testing in a large urban comprehensive cancer center over a 20-year period.
Methods
The population included 3,537 unrelated individuals who underwent genetic testing from January 1999 to October 2019 at the Karmanos Cancer Institute. We estimated the prevalence of pathogenic variants and VUS and evaluated associations with race and ethnicity for African American (AA), Arab, AJ and Hispanic individuals compared to Non-Hispanic Whites (NHW). We used multivariable models to adjust for other predictors of pathogenic variants. We also reported the most common pathogenic variants by racial and ethnic group.
Results
The racial and ethnic breakdown of our population was: NHW (68.9%), AA (20.3%), AJ (2.5%), Arab (2.2%), Hispanic (1.0%), Asian Pacific Islander, Native American/Alaskan Native (4.7%), and < 1% unknown. The overall prevalence of pathogenic variants in BRCA1/2 was 8.9% and the prevalence of VUS was 5.6%. Compared to NHW, there were no racial or ethnic differences in the rate of pathogenic variants. However, AA individuals were more likely to have VUS in BRCA1 (adjusted OR 2.43, 95% CI 1.38–4.28) and AJ were more likely to have VUS in BRCA2 (adjusted OR 3.50, 95% CI 1.61–6.58).
Conclusion
These results suggest the continued need for genetic testing and variant reclassification for individuals of all racial and ethnic groups.
... [13] Similarly, other recurring variants have been reported in different populations including Europeans and Hispanics. [10,[14][15][16][17] However, unlike the AJ population, speci c mutation prevalence is less clearly de ned in other racial and ethnic groups. As with pathogenic variants, ethnicity-speci c differences have also been observed in the prevalence of variants of uncertain signi cance (VUS). ...
Purpose: The prevalence of pathogenic variants in BRCA1 and BRCA2 in populations other than Ashkenazi Jewish (AJ) is not well defined. We describe the racial and ethnic-specific prevalence of BRCA1/2 pathogenic variants and variants of uncertain significance (VUS) among individuals referred for genetic testing in a large urban comprehensive cancer center over a 20-year period.
Methods: The population included 3,537 unrelated individuals who underwent genetic testing from January 1999 to October 2019 at the Karmanos Cancer Institute. We estimated the prevalence of pathogenic variants and VUS and evaluated associations with race and ethnicity for African American (AA), Arab, AJ and Hispanic individuals compared to Non-Hispanic Whites (NHW). We used multivariable models to adjust for other predictors of pathogenic variants. We also reported the most common pathogenic variants by racial and ethnic group.
Results: The racial and ethnic breakdown of our population was: NHW (68.9%), AA (20.3%), AJ (2.5%), Arab (2.2%), Hispanic (1.0%), Asian Pacific Islander, Native American/Alaskan Native (4.7%), and <1% unknown. The overall prevalence of pathogenic variants in BRCA1/2 was 8.9% and the prevalence of VUS was 5.6%. Compared to NHW, there were no racial or ethnic differences in the rate of pathogenic variants. However, AA individuals were more likely to have VUS in BRCA1 (adjusted OR 2.43, 95% CI 1.38-4.28) and AJ more likely to have VUS in BRCA2 (adjusted OR 3.50, 95% CI 1.61-6.58).
Conclusion: These results suggest the continued need for genetic testing and variant reclassification for individuals of all race and ethnic groups.
... Regarding the Northern European countries, the most common BRCA1 founder mutations detected among the Norwegian population were represented by 1675delA, 816delGT, 3347delAG and 1135insA (109)(110)(111). Furthermore, several BRCA1/2 mutations have been exclusively detected in individuals born in Finland, including IVS1˚+3A>G and R1443X for BRCA1 and IVS23+1G>A, 7708C>T and T8555G for BRCA2 (112). ...
Breast and ovarian cancer represent two of the most common tumor types in females worldwide. Over the years, several non‑modifiable and modifiable risk factors have been associated with the onset and progression of these tumors, including age, reproductive factors, ethnicity, socioeconomic status and lifestyle factors, as well as family history and genetic factors. Of note, BRCA1 and BRCA2 are two tumor suppressor genes with a key role in DNA repair processes, whose mutations may induce genomic instability and increase the risk of cancer development. Specifically, females with a family history of breast or ovarian cancer harboring BRCA1/2 germline mutations have a 60‑70% increased risk of developing breast cancer and a 15‑40% increased risk for ovarian cancer. Different databases have collected the most frequent germline mutations affecting BRCA1/2. Through the analysis of such databases, it is possible to identify frequent hotspot mutations that may be analyzed with next‑generation sequencing (NGS) and novel innovative strategies. In this context, NGS remains the gold standard method for the assessment of BRCA1/2 mutations, while novel techniques, including droplet digital PCR (ddPCR), may improve the sensitivity to identify such mutations in the hereditary forms of breast and ovarian cancer. On these bases, the present study aimed to provide an update of the current knowledge on the frequency of BRCA1/2 mutations and cancer susceptibility, focusing on the diagnostic potential of the most recent methods, such as ddPCR.
... Even though BRCA1 sequencing of HBOC patients has been performed in Norway since late 1990s, previous studies characterizing BRCA1 variants in Norway have included only specific regions of the country [20][21][22]24]. This study is the first to include BRCA1 variant data from all four medical genetic departments in Norway, and gives a complete overview of the Norwegian BRCA1 variant spectrum. ...
Pathogenic germline variants in Breast cancer susceptibility gene 1 ( BRCA1 ) predispose carriers to hereditary breast and ovarian cancer (HBOC). Through genetic testing of patients with suspected HBOC an increasing number of novel BRCA1 variants are discovered. This creates a growing need to determine the clinical significance of these variants through correct classification (class 1–5) according to established guidelines. Here we present a joint collection of all BRCA1 variants of class 2–5 detected in the four diagnostic genetic laboratories in Norway. The overall objective of the study was to generate an overview of all BRCA1 variants in Norway and unveil potential discrepancies in variant interpretation between the hospitals, serving as a quality control at the national level. For a subset of variants, we also assessed the change in classification over a ten-year period with increasing information available. In total, 463 unique BRCA1 variants were detected. Of the 126 variants found in more than one hospital, 70% were interpreted identically, while 30% were not. The differences in interpretation were mainly by one class (class 2/3 or 4/5), except for one larger discrepancy (class 3/5) which could affect the clinical management of patients. After a series of digital meetings between the participating laboratories to disclose the cause of disagreement for all conflicting variants, the discrepancy rate was reduced to 10%. This illustrates that variant interpretation needs to be updated regularly, and that data sharing and improved national inter-laboratory collaboration greatly improves the variant classification and hence increases the accuracy of cancer risk assessment.
... Previously, we have discussed that the probability for a random pathogenic variant to become frequent increases with inbreeding in expanding populations [11], which indeed is the history for the Norwegian population through the last 600 years. ...
Background: We have previously demonstrated that the Norwegian frequent pathogenic BRCA1 (path_BRCA1) variants are caused by genetic drift and recurrent de-novo mutations. We here examined the penetrance of frequent path_BRCA1 variants in fertile ages as a surrogate marker for fitness. Material and methods: We conducted an observational prospective study of penetrance for cancer in Norwegian female carriers of frequent path_BRCA1 variants, and compared our observed results to penetrance of infrequent path_BRCA1 variants and to average penetrance of path_BRCA1 variants reported by others. Results: The cumulative risk for breast cancer at 45 years in carriers of frequent path_BRCA1 variants was 20% (94% confidence interval 10–30%), compared to 35% (95% confidence interval 22–48%) in carriers of infrequent path_BRCA1 variants (p = 0.02), and to the 35% (confidence interval 32–39%) average for path_BRCA1 carriers reported by others (p = 0.0001). Discussion and conclusion: Carriers of the most frequent Norwegian path_BRCA1 variants had low incidence of cancer in fertile ages, indicating a low selective disadvantage. This, together with the variant locations being hotspots for de novo mutations and subject to genetic drift, as previously described, may have caused their high prevalence today. Besides being of theoretical interest to explain the phenomenon that a few path_BRCA1 variants are frequent, the later onset of breast cancer associated with the most frequent path_BRCA1 variants may be of interest for carriers who have to decide if and when to select prophylactic mastectomy.
... The c.1016dupA mutation was detected in Moroccan families [23]. It has previously been described as one of four founder mutations originating from the Eastern population of Norway [42]. In contrast to other Norwegian founder mutations, the c.1016dupA has also been reported in other ethnic groups. ...
Background:
The contribution of BRCA1 mutations to both hereditary and sporadic breast and ovarian cancer (HBOC) has not yet been thoroughly investigated in MENA.
Methods:
To establish the knowledge about BRCA1 mutations and their correlation with the clinical aspect in diagnosed cases of HBOC in MENA populations. A systematic review of studies examining BRCA1 in BC women in Cyprus, Jordan, Egypt, Lebanon, Morocco, Algeria, and Tunisia was conducted.
Results:
Thirteen relevant references were identified, including ten studies which performed DNA sequencing of all BRCA1 exons. For the latter, 31 mutations were detected in 57 of the 547 patients ascertained. Familial history of BC was present in 388 (71%) patients, of whom 50 were mutation carriers. c.798_799delTT was identified in 11 North African families, accounting for 22% of total identified BRCA1 mutations, suggesting a founder allele. A broad spectrum of other mutations including c.68_69delAG, c.181T>G, c.5095C>T, and c.5266dupC, as well as sequence of unclassified variants and polymorphisms, was also detected.
Conclusion:
The knowledge of genetic structure of BRCA1 in MENA should contribute to the assessment of the necessity of preventive programs for mutation carriers and clinical management. The high prevalence of BC and the presence of frequent mutations of the BRCA1 gene emphasize the need for improving screening programs and individual testing/counseling.
... Danish population shares some founder mutations 3450delCAAG [33,191] and A1708E (polymorphism) [33] Exons 9-12 del [97] 3034delACAA [33] 3450delCAAG [191] Exons 9-12 del (Mexican founder) [ [194] c.5114 5117delTAAA c.2639 2640delTG [194] - [22,195,196] 6880 insG and 3034 del AAAC [197] Maybe 5382insC [195] Russia 5382insC [130,131], 4153delA [129] 185delAG [128] 695insT, 1528del4, 9318del4, S1099X [131] 5382insC [131] Japan c.307T>A [115] 5802delAATT, 8732C>A, c.2835C>A [114,115] c.188T>A, c.2800C>T [110] c.2835C>A, c.307T>A, 5802delAATT [114,115] Korea 509C>A, c.2333delC, c.4065 4068delTCAA 3746 3747insA (c.3627 3628insA ), 5199G>T (c.5080G>T) [110,198] c.7480C>T, 1627A.T 3972delTGAG, 7708C.T [110,111,198,199] c.7480C>T [110,111,199] China 3478del5, 5589del8, 1100delAT, 2778G>A, 3552C>T [117,118] [201], 3300delA, T320G [202] c.5191C>A [203] 2670delC, 3073delT, and 6696-7delTC [204] 3300delA, T320G 8 BioMed Research International --Philippines 5454delC [208] 4265delCT and 4859delA [208] 5454delC, 4265delCT, 4859delA [208] Indonesia (in South eastern Asia) -6775G>T, p.Glu2183X, c.2699 2704delTAAATG [211] c.2699 2704delTAAATG [211] c.3381delT/3609delT, c.7110delA/7338delA, c.7235insG/7463insG [216] c.798 799delTT [146] Western cape of South Africa c.1504 1508del [145] c.2826 2829del, c.6447 6448dup, c.5771 5774del, 5999del4 [145] 5999del4 [145] with Norwegian and Swedish peoples that could propose a unique ancestry for these three Scandinavian countries [38,49]. The most frequent mutations of BRCA1 gene which are replicated in multiple Norwegian studies are 1135insA, 1675delA, 816delGT, 3203del11, and 3347delAG [50,51]. The first two alterations are founder mutations of BRCA1 gene in Norwegian population and it has been shown that they have less penetrance in them compared to Ashkenazi Jews [52,53]. ...
Breast cancer (BC) is the most common cancer of women all over the world. BRCA1 and BRCA2 gene mutations comprise the most important genetic susceptibility of BC. Except for few common mutations, the spectrum of BRCA1 and BRCA2 mutations is heterogeneous in diverse populations. 185AGdel and 5382insC are the most important BRCA1 and BRCA2 alterations which have been encountered in most of the populations. After those Ashkenazi founder mutations, 300T>G also demonstrated sparse frequency in African American and European populations. This review affords quick access to the most frequent alterations among various populations which could be helpful in BRCA screening programs.
... For Rogaland kan forklaringen på den forholdsvis høye letaliteten vaere at det er opphopning av BRCA1-baerere (35). Disse baererne har betydelig dårligere prognose enn dem som ikke har dette genet. ...
... In order to assess whether a recurrent germline mutation is a founder one, it is important to show that it has appeared only once in a common ancestor. Several founder mutations of the BRCA1 gene have been identified in individuals of many different ancestries (7)(8)(9)(10)(11)(12)(13)(14). A recent study in the Greek population has identified p.Gly1738Arg as a Greek founder mutation (15). ...
Pertesi M, Konstantopoulou I, Yannoukakos D. Haplotype analysis of two recurrent genomic rearrangements in the BRCA1 gene suggests they are founder mutations for the Greek population.
The deletions of 4.4 and 3.2 kb identified in exons 24 and 20, respectively, are two of the four most common mutations in the BRCA1 gene in Greek breast cancer patients. They have been reported previously six and three times, respectively, in unrelated Greek families. A total of 11 more families have been identified in the present study. In order to characterize these recurrent mutations as founder mutations, it is necessary to identify the disease-associated haplotype and prove that it is shared by all the mutation carriers, suggesting that it occurred only once in a common ancestor. Haplotype analysis was performed on 24 mutation carriers and 66 healthy individuals using 10 short tandem repeat markers located within and flanking the BRCA1 gene locus, spanning a 5.9 Mb interval. Results indicate that most of the carriers of the exon 24 deletion share a common core haplotype ‘4-7-6-6-1-3’ between markers D17S951 and D17S1299, for a stretch of 2.9 Mb, while the common haplotype for the exon 20 deletion is ‘6-7-4-2-6-7-1-3’ between markers D17S579 and D17S1299, for a stretch of 3.9 Mb. Both genomic rearrangements in BRCA1 gene are Greek founder mutations, as carriers share the same, for each mutation, disease-associated haplotype, suggesting the presence of a distinct common ancestor for both mutations.
... Due to the population history, with decimation of the population during the Bubonic plagues in the medieval age, isolation of the remaining population in islands of geographically separated areas, and the rapid population growth during the following centuries, strong founder effects are believed to have developed in many hereditary diseases in Norway. Strong local founder effects have been demonstrated in some hereditary diseases such as BRCA 1related breast and ovarian cancer (Moller et al, 2001). Local variation in mutation frequency may well exist also for genes involved in HI. ...
Severe to profound hearing impairment (HI) is estimated to affect around 1/2000 young children. Advances in genetics have made it possible to identify several genes related to HI. This information can cast light upon prognostic factors regarding the outcome in cochlear implantation, and provide information both for scientific and genetic counselling purposes. From 1992 to 2005, 273 children from 254 families (probands) were offered cochlear implants in Norway. An evaluation of the causes of HI, especially regarding the genes GJB2, GJB6, SLC26A4, KCNQ1, KCNE1, and the mutation A1555G in mitochondrial DNA was performed in 85% of the families. The number of probands with unknown cause of HI was thus reduced from 120 to 68 (43% reduction). Ninety-eight (46%) of the probands had an identified genetic etiology of their HI. A relatively high prevalence of Jervell and Lange-Nielsen syndrome was found. The main causes of severe and profound HI were similar to those found in other European countries. GJB2 mutations are a common cause of prelingual HI in Norwegian cochlear implanted children.
... Indeed, it is easier in this type of population to extrapolate the total number of carriers of particular mutations, to standardize phenotypic assessment and to facilitate the definition of the phenotype(s) associated with disease-causing variations. When these populations show founder effects, it is further easier to identify high-risk families and to determine the contribution of the mutated genes to the incidence of the disorder in the population under study (19)(20)(21)(22). ...
Primary open-angle glaucoma (POAG) is a complex disorder characterized by a progressive and treatable degeneration of the optic nerve. TIGR/myocilin (MYOC) gene mutations are found in approximately 4% of all POAG patients. Populations with frequent founder effects, such as the French-Canadians, offer unique advantages to implement genetic testing for the disorder. To assess molecular diagnosis for POAG in this population, we determined the prevalence of TIGR/MYOC mutations in 384 unrelated glaucoma patients, 38 ocular hypertensive subjects and 18 affected families (180 patients). We further analyzed the clinical features associated with these variations. Nine coding sequence variants were defined as mutations causing mostly, but not exclusively, POAG. Four families segregated distinct mutations (Gly367Arg, Gln368Stop, Lys423Glu and Pro481Leu), while 14 unrelated glaucoma patients harbored six known mutations (Thr293Lys, Glu352Lys, Gly367Arg, Gln368Stop, Lys423Glu and Ala445Val) and two novel (Ala427Thr and Arg126Trp). The frequencies of these mutations were respectively 3.8% and 22.2% in the unrelated and family studies. The Gly367Arg and Lys423Glu variants caused the earliest ages at onset. When achievable, assessment of relatives of unrelated mutation carriers showed the Arg126Trp and Gly367Arg to be familial. Characteristic allele signatures, indicative of specific founder effects, were observed for five of the six mutations conveyed by at least two patients. Recombination probability estimates suggested that the French-Canadian population had most probably inherited these six mutations from 7-10 Québec settlers. Our data demonstrated that genetic screening for TIGR/MYOC mutations should be offered to glaucoma families and to close relatives of unrelated patients aware of a family history for the disorder.
... 4 Depending on the population, 3.3-13.5% of epithelial ovarian cancer cases are explained by germline mutations of the BRCA1 gene, the BRCA2 gene probably contributes to a lesser extent. [5][6][7][8][9][10][11][12][13] Multiparity, lactation, use of oral contraceptives, tubal ligation and hysterectomy are associated with decreased risk of ovarian carcinoma. 14,15 The etiology of ovarian carcinoma is unknown but frequent ovulation and hormonal factors have been suggested to play a role in its pathogenesis. ...
Ovarian carcinoma is the fourth most common cause of cancer death in women. The cause and pathogenesis of this disease has remained obscure. Galactose, the hydrolyzing product of the milk sugar lactose, has been hypothesized to be toxic to ovarian epithelial cells and consumption of dairy products and lactase persistence has been suggested to be a risk factor for ovarian carcinoma. In adults, downregulation of lactase depends on a variant C/T-13910 at the 5' end of the lactase gene. To explore whether lactase persistence is related to the risk of ovarian carcinoma we determined the C/T-13910 genotype in a cohort of 782 women with ovarian carcinoma. The C/T-13910 genotype was defined by solid phase minisequencing from 327 Finnish, 303 Polish, 152 Swedish patients and 938 Finnish, 296 Polish and 97 Swedish healthy individuals served as controls. Lactase persistence did not associate significantly with increased risk for ovarian carcinoma in the Finnish (odds ratio [OR]=0.77, 95% confidence interval [CI]=0.57-1.05, p=0.097), in the Polish (OR=0.95, 95% CI=0.68-1.33, p=0.75), or in the Swedish populations (OR=1.63, 95% CI=0.65-4.08, p=0.29). Our results do not support the hypothesis that lactase persistence increases the ovarian carcinoma risk. On the contrary, lactase persistence may decrease the ovarian carcinoma risk at least in the Finnish population.
... In some families, no living family member with cancer was available for mutation testing. All FBOC families with a woman alive with breast cancer were tested for a mutation, but did not carry any of the frequent Norwegian BRCA mutations [24]. Each woman included had been informed at genetic counseling that a mutation was assumed to cause inherited cancer in the family but could not be demonstrated, and as sisters or daughters of affected relatives they had a 50% chance of having the mutation. ...
To examine psychological distress in women at risk of familial breast-ovarian cancer (FBOC) or hereditary non-polyposis colorectal cancer (HNPCC) with absence of demonstrated mutations in the family (unknown mutation).
Two-hundred and fifty three consecutive women at risk of FBOC and 77 at risk of HNPCC and with no present or past history of cancer. They were aware of their risk and had received genetic counseling. Comparisons were made between these two groups, normal controls, and women who were identified to be BRCA1 mutation carriers. The questionnaires Beck Hopelessness Scale (BHS), General Health Questionnaire (GHQ-28), Hospital Anxiety and Depression Scale (HADS) and Impact of Event Scale (IES) were employed to assess psychological distress.
No significant differences concerning psychological distress were observed between women with FBOC and women with HNPCC. Compared to mutation carriers for BRCA1, the level of anxiety and depression was significantly higher in the FBOC group with absence of demonstrated mutation. Compared to normal controls, the level of anxiety was higher, while the level of depression was lower in the groups with unknown mutation.
Women in the absence of demonstrated mutations have higher anxiety and depression levels than women with known mutation-carrier status. Access to genetic testing may be of psychologically benefit to women at risk for FBOC or HNPCC.
... Several studies have demonstrated that BRCA1 and BRCA2 disease-causing mutations are confined to certain ethnic populations and geographic areas [5, 6]. Some populations are characterized by a very short number of BRCA1 and BRCA2 pathological alterations, for instance three mutations in Ashkenazi Jews [7, 8] and only one in Icelanders [9] account for almost all alterations detected in these ethnic groups; in the same line, three BRCA1 mutations account for 50% of all pathological alterations observed in Norwegians [10]. On the other hand, other countries appear to exhibit a much broader BRCA1/2 mutation spectrum. ...
127 Greek breast/ovarian cancer families were screened for germline BRCA1/2 mutations by dHPLC followed by direct sequencing. Our results indicated 16 and 5 breast/ovarian cancer families bearing deleterious mutations in the BRCA1 and BRCA2 genes, respectively. Two novel BRCA2 germline mutations (G4X and 3783del10) are reported here for the first time. Subsequent compilation of our present findings with previously reported mutation data reveals that in a total of 287 Greek breast/ovarian cancer families, 46 and 13 carry a deleterious mutation in BRCA1 and BRCA2, respectively. It should be noted that two BRCA1 mutations, 5382insC and G1738R, both located in exon 20, account for 46% of the families found to carry a mutation. Based on our mutation analysis results, we propose here a hierarchical, cost-effective BRCA1/2 mutation screening protocol for individuals of Greek ethnic origin. The suggested protocol can impact on the clinical management of breast-ovarian cancer families on a national healthcare system level.
Hereditary breast cancer (HBC) is a heterogeneous disease caused by mutations in genes characterized by ethnic specifcity. The clinical heterogeneity of this disease signifcantly complicates its diagnosis. The use of high-throughput sequencing is one of the approaches that allow the search for genes and their variants associated with the development of HBC. The purpose of the study was to search for new genes associated with HBC in the understudied ethnic groups of Siberia by using whole exome sequencing (WES).
Material and Methods. WES was performed on a cohort of 16 probands with BC (Tuvan, Yakut, Altai ethnos). The study material was genomic DNA isolated from peripheral blood leukocytes. Libraries were prepared using a BGI Optimal DNA Library Prep kit. An Agilent SureSelect Human All Exon V6 kit was used for hybridization. High-throughput sequencing was performed on a DNA nanoball sequencing platform (DNBSeq-G400).
Results . In the overall group of patients with signs of HBC, pathogenic variants were detected in 12.5 % of cases (2/16). For the frst time, BRCA1 (rs80357635) pathogenic variant was identified in a young patient with metachronous BC (Yakut ethnic group). A pathogenic variant of the ATM gene (rs780619951 NM_000051:exon16:c.C2413T:p.R805X) was identified in a young patient with BC (Tuvinian ethnic group). A pathogenic variant of the TDP2 c.G4T:p.E2X, rs770844602 gene (DNA repair gene) was identified for the frst time in a Tuvan BC patient (metachronous) with a family history, but its contribution to HBC remains to be proven. The TDG gene variant (rs764159587 NM_001363612:exon7:c.536dupA:p.E179fs) found in the Tuvan ethnic group and affecting splicing (SpliceAI: 0.580) requires special attention.
Conclusion . This report is the frst to describe the germinal variant in the BRCA1 (rs80357635) gene in the Yakut ethnic group. Further studies are required to confrm pathogenicity of germinal variants in non-well studied genes TDP2 , TDG in ethnic BC patients.
Background/Aim: Certain germline pathogenic variants (PVs), known as founder mutations, have been frequently observed in specific regions and ethnic groups. In Japan, several pathogenic variants of BRCA1/2 have been identified as founder mutations, with their distribution varying across different regions. This retrospective study aimed to further investigate the detailed distribution and correlation between genotype and clinical features among breast cancer patients. Patients and Methods: This study was conducted at Kobe University Hospital and three collaborating institutions. It included breast cancer patients who underwent BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021, and were found to have germline PVs. Clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those with other PVs. Additionally, the detection rate of BRCA2 c.5576_5579del was compared with that observed in a previous report. Results: A total of 38 breast cancer patients were included; PVs in BRCA1 and BRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2 c.5576_5579del carriers. BRCA2 c.5576_5579del carriers were more likely to develop triple negative breast cancers among all BRCA2 PV carriers. BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. Conclusion: BRCA2 c.5576_5579del was detected with a particularly high frequency in Hyogo Prefecture, especially in Kakogawa city. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization.
The aim of the present study was to describe the genetic structure of the Norwegian population using genotypes from 6369 unrelated individuals with detailed information about places of residence. Using standard single marker- and haplotype-based approaches, we report evidence of two regions with distinctive patterns of genetic variation, one in the far northeast, and another in the south of Norway, as indicated by fixation indices, haplotype sharing, homozygosity and effective population size. We detect and quantify a component of Uralic Sami ancestry that is enriched in the North. On a finer scale, we find that rates of migration have been affected by topography like mountain ridges. In the broader Scandinavian context, we detect elevated relatedness between the mid- and northern border areas towards Sweden. The main finding of this study is that despite Norway's long maritime history and as a former Danish territory, the region closest to mainland Europe in the south appears to have been the most isolated region in Norway, highlighting the open sea as a barrier to gene flow.
BRCA1 gene mutations account for about 25-28% of hereditary Breast Cancer as BRCA1 is included in the category of high penetrance genes. Except for few commonmutations, there is a heterogenous spectrum of BRCA1 mutations in various ethnic groups. 185AGdel and 5382ins Care the most common BRCA1 alterations (founder mutations) which have been identified in most of the population. This review has been compiled with an aim to consolidate the information on genetic variants reported in BRCA1 found in various ethnic groups, their functional implications if known; involvement of BRCA1 in various cellular pathways/processes and potential BRCA1 targeted therapies. The pathological variations of BRCA1 vary among different ethical groups. A systematic search in PubMed and Google scholar for the literature on BRCA1 gene was carried out to figure out structure and function of BRCA1 gene. BRCA1 is a large protein having 1863 amino acids with multiple functional domains and interacts with multiple proteins to carry out various crucial cellular processes. BRCA1 plays a major role in maintaining genome integrity, transcription regulation, chromatin remodeling, cell cycle checkpoint control, DNA damage repair, chromosomal segregation, and apoptosis. Studies investigating the phenotypic response of mutant BRCA1 protein and comparing it to wildtype BRCA1 protein are clinically important as they are involved in homologous recombination and other repair mechanisms. These studies may help in developing more targetted therapies, detecting novel interacting partners, identification of new signaling pathways that BRCA1 is a part of or downstream target genes that BRCA1 affects.
Cancer is a common non-communicable disease worldwide, although it exhibits differential population trends in incidence and mortality rates. The differences relate to population structure, environmental risk factors as well as health system organization. This article discusses the potential impact of genetic testing on population health, focusing in particular on the mutational spectrum of breast cancer susceptibility genes in diverse populations. We identify the need for improved access to, and increased investment in, comprehensive cancer risk assessment and genetic testing as well as cancer control measures that take into account lifestyle, environmental, and social factors in understudied minority groups.
Inherited mutations in high-risk breast cancer-predisposing genes explain approximately 10 % of all breast cancer cases. Most of these mutations are in the BRCA1 and BRCA2 genes, as part of hereditary breast and ovarian cancer (HBOC). Others are in genes associated with syndromes which include a wider spectrum of malignancies and/or distinct clinical features. Molecular analysis, guided by clinical criteria and application of risk assessment models, currently reveal the underlying cause in roughly half of hereditary breast cancer families. Women who have inherited mutations in the HBOC genes have a high lifetime risk for both breast cancer and ovarian cancer. In BRCA1 and BRCA2 carriers, effective surveillance and prevention measures (such as risk-reduction salpingo-oophorectomy) reduce morbidity and mortality, and mutation status can enable targeted therapy (such as PARP inhibitors).
A large number of cancer predisposing BRCA1/BRCA2 mutations have been reported, with a wide variety among populations. In some restricted groups, specific germline mutations in these tumor suppressor genes have been found with high predominance, due to a founder effect. We focused our review on the Italian founder mutations. The first Italian BRCA1 founder mutation, 5083del19, was found in Calabria: the presence of common allele in all carriers of this mutation (also in families with Calabrian origin living in other parts of Italy) confirmed its founder effect. The same BRCA1 mutation was identified in the Sicilian population, but only the haplotype analysis can reveal the common ancestor of these groups. Another BRCA1 founder mutation, 4843delC, was found in Sicily. Four distinct BRCA1 mutations are attributable to families original from Tuscany: 3348delAG, 3285delA, 1499insA and 5183delTGT; the latter has been shown to be a founder mutation from North-Eastern Italy. The first BRCA2 mutation was identified in Sardinia, 8765delAG, a mutation already described as a founder mutation in Jewish-Yemenite families and also in French-Canadian population but with independent origins of carriers in these three populations. BRCA2 3951del3 and BRCA1 917delTT have been described as founder mutations in Middle Sardinia and in South and Middle Sardinia, respectively. Studies regarding prevalence and penetrance of founder mutations can allow to quantify the degree of homogeneity within a population and can surely help the geneticist and oncologist to simplify their choices in the genetic testing on high-risk families, on the basis of their ethnical origin.
Ovarian cancer survival rates have improved only slightly in recent decades; however, treatment of this disease is expected to undergo rapid change as strategies incorporating molecular-targeted therapies enter clinical practice. Carriers of deleterious mutations (defined as a harmful mutation) in either the BRCA1 or BRCA2 gene (BRCAm) have a significantly increased risk of developing ovarian cancer. Epidemiology data in large (>500 patients) unselected ovarian cancer populations suggest that the expected incidence rate for BRCAm in this population is 12-14 %. Patients with a BRCAm are typically diagnosed at a younger age than those without a BRCAm. Associations with BRCAm vary according to ethnicity, with women of Ashkenazi Jewish descent being 10 times more likely to have a BRCAm than the general population. In terms of survival, patients with invasive epithelial ovarian cancer who have a BRCAm may have improved overall survival compared with patients who do not carry a BRCAm. Although genetic testing for BRCAm remains relatively uncommon in ovarian cancer patients, testing is becoming cheaper and increasingly accessible; however, this approach is not without numerous social, ethical and policy issues. Current guidelines recommend BRCAm testing in specific ovarian cancer patients only; however, with the emergence of treatments that are targeted at patients with a BRCAm, genetic testing of all patients with high-grade serous ovarian cancer may lead to improved patient outcomes in this patient population. Knowledge of BRCAm status could, therefore, help to inform treatment decisions and identify relatives at increased risk of developing cancer.
Hereditary Haemorrhagic Telangiectasia (HHT, Osler-Weber-Rendu disease) is an autosomal dominant inherited disease defined by the presence of epistaxis and mucocutaneous telangiectasias and arteriovenous malformations (AVMs) in internal organs. In most families (~85 %), HHT is caused by mutations in the ENG (HHT1) or the ACVRL1 (HHT2) genes. Here we report the results of genetic testing of 113 Norwegian families with suspected or definite HHT. Variants in ENG and ACVRL1 were found in 105 families (42 ENG, 63 ACVRL1), including six novel variants of uncertain pathogenic significance. Mutation types were similar to previous reports with more missense variants in ACVRL1 and more nonsense, frameshift and splice site mutations in ENG. Thirty-two variants were novel in this study. The preponderance of ACVRL1 mutations was due to founder mutations, specifically: c.830C>A (p.Thr277Lys) which was found in 24 families from the same geographical area of Norway. We discuss the importance of founder mutations and present a thorough evaluation of missense and splice site variants.
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BRCA1/BRCA2 genes were screened in 117 patients with breast cancer by sequencing. Fourteen percent of patients tested positive for BRCA1/BRCA2 mutations. Four frame shift mutations, four pathogenic missense mutations, and 25 different sequence variations were detected. BRCA mutation positivity was significantly associated with Ki67 (p = .001). BRCA protein expressions were decreased in the patients harboring important mutations and polymorphisms (BRCA1;P508stop, V1740G, Q1182R, Q1756P and BRCA2;V2466A) related with disease. Our findings contribute significantly to the types of germline BRCA1/BRCA2 mutations and their biological effects in Turkish women. These data could help guide the management of BRCA1/BRCA2 mutation-carrying patients when considering breast-conserving therapy.
Objective
The aim of this work was to pinpoint familial breast and/or ovarian cancer risk. Clinical cancer genetics include: diagnostic cancer genetics, cancer genetic counseling and management of women at high risk of developing breast and/or ovarian cancer.
Material and methods
An update of documented data was performed in order to assess our current knowledge about inherited breast-ovarian cancer.
Results
Most breast cancers (BC) are sporadic while 5-10% are estimated to be due to an inherited predisposition. Rare autosomal dominant alteration in two genes, BRCA1 and BRCA2, which confer a high risk of developing BC and ovarian cancer (OC), are likely to account for most families with multiple cases of early-onset BC and OC, but only 3-4% of all BC. The estimations of their prevalence and penetrance vary greatly, depending on the population studied, the study design, statistical methods and the sensivity of technical methods for detection of mutations. Penetrance can be very high, but incomplete (maximum 80%). Penetrance and age at onset of the same mutation show great variability within and between BC families. This could be due to the effects of other genetic as well as non-genetic factors that are being studied. The heterogeneity of families makes the identification of other high-risk genes difficult. Additive effects of several susceptibility genes could explain much more BC in the general population (polygenic models).
Molecular diagnoses have become feasible. Specific consultations in oncogenetics help clinicians and patients understand hereditary components, establish molecular diagnoses, provide guidelines for a better surveillance of people at high risk of developing BC, OC or both and reassure the mutation non-carriers. The strategies of management and treatment of BC and OC in mutation carriers remain under discussion and it is is difficult to choose preventive options.
Conclusion
Inherited BC or OC due to a mutation in BRCA1 or BRCA2 are rare in the general population. However, women and men have the right to be informed of the possibilities concerning presymptomatic testing, risk assessment, surveillance, prevention and psychological support with respect to the potential benefits and limitations.
Other large prospective studies are needed to validate rapidly the methods of surveillance and prevention in this group at “high risk” in order to adapt them to very large populations. However, predictive medicine should be used with care.
Worldwide variation in the distribution of BRCA mutations is well recognised, and for the Moroccan population no comprehensive studies about BRCA mutation spectra or frequencies have been published. We therefore performed mutation analysis of the BRCA1 gene in 121 Moroccan women diagnosed with breast cancer. All cases completed epidemiology and family history questionnaires and provided a DNA sample for BRCA testing. Mutation analysis was performed by direct DNA sequencing of all coding exons and flanking intron sequences of the BRCA1 gene. 31.6 % (6/19) of familial cases and 1 % (1/102) of early-onset sporadic (< 45 years) were found to be associated with BRCA1 mutations. The pathogenic mutations included two frame-shift mutations (c.798_799delTT, c.1016dupA), one missense mutation (c.5095C>T), and one nonsense mutation (c.4942A>T). The c.798_799delTT mutation was also observed in Algerian and Tunisian BC families, suggesting the first non-Jewish founder mutation to be described in Northern Africa. In addition, ten different unclassified variants were detected in BRCA1, none of which were predicted to affect splicing. Most unclassified variants were placed in Align-GVGD classes suggesting neutrality. c.5117G>C involves a highly conserved amino acid suggestive of interfering with function (Align-GVGD class C55), but has been observed in conjunction with a deleterious mutation in a Tunisian family. These findings reflect the genetic heterogeneity of the Moroccan population and are relevant to genetic counselling and clinical management. The role of BRCA2 in BC in Morocco is also under study. Our study is the first molecular investigation of the role of the BRCA genes in breast and ovarian cancer in Morocco.
Detection of mutations in hereditary breast and ovarian cancer-related BRCA1 and BRCA2 genes is an effective method of cancer prevention and early detection. Different ethnic and geographical regions have different BRCA1 and BRCA2 mutation spectrum and prevalence. Along with the emerging targeted therapy, demand and uptake for rapid BRCA1/2 mutations testing will increase in a near future. However, current patients selection and genetic testing strategies in most countries impose significant lag in this practice. The knowledge of the genetic structure of particular populations is important for the developing of effective screening protocol and may provide more efficient approach for the individualization of genetic testing. Elucidating of founder effect in BRCA1/2 genes can have an impact on the management of hereditary cancer families on a national and international healthcare system level, making genetic testing more affordable and cost-effective. The purpose of this review is to summarize current evidence about the BRCA1/2 founder mutations diversity in European populations.
Breast cancer is the most common cancer among women in Western countries, with about 180,000 new cases and 40,000 deaths occurring
annually in the United States. Epidemiologic factors consistently associated with breast cancer risk include a family history
of breast cancer, breast biopsy features, and hormonal risk factors such as age at menarche, parity, and age at first live
birth. After female gender and age, family history of breast cancer is the most significant risk factor. In a meta-analysis
of family history of breast cancer as a risk factor, the relative risk ranged from 1.5 for a second-degree relative to 3.6
for a mother and sister with breast cancer.1 Relative risks are significantly influenced by the degree of relationship of affected relatives and their age of breast cancer
onset, with closer degrees of relationship and younger age of onset conveying higher risks. An analysis of family history
as a risk factor using data from the Swedish Family-Cancer Database showed a populationattributable fraction of about 11%.2
The two major breast cancer susceptibility genes, BRCA1 and BRCA2, account for the majority of familial breast–ovarian cancer, but only a modest proportion of breast cancer families without ovarian or male breast cancer. Search for additional breast cancer genes with traditional linkage analysis has so far been unsuccessful, probably due to genetic heterogeneity. Pooling of families of different ethnical, cultural, and geographical origin proved to be a useful approach when identifying BRCA1 and BRCA2, but for genes mutated only in specific populations it is important not to introduce locus heterogeneity by pooling. Genetic heterogeneity can possibly be circumvented by using objective means, such as tumour histopathology or gene expression profiling, for subclassification of families prior to linkage analysis. Also, additional breast cancer genes can be identified by further characterization of the function of BRCA1 and BRCA2 and their interacting proteins.
Møller P, Mæhle L, Vabø A, Clark N, Sun P, Narod SA. Age-specific incidence rates for breast cancer in carriers of BRCA1 mutations from Norway.
Incidence rates of breast cancer among women with a BRCA1 mutation vary according to their reproductive histories and country of residence. To measure cancer incidence, it is best to follow-up cohort of healthy women prospectively. We followed up a cohort of 675 women with a BRCA1 mutation who did not have breast or ovarian cancer before inclusion and who had a normal clinical examination and mammography at first visit. After a mean of 7.1 years, 98 incident cases of breast cancer were recorded in the cohort. Annual cancer incidence rates were calculated, and based on these, a penetrance curve was constructed. The average annual cancer risk for the Norwegian women from age 25 to 70 was 2.0%. Founder mutations had lower incidence rate (1.7%) than less frequent mutations (2.5%) (p = 0.03). The peak incidence (3.1% annual risk) was observed in women from age 50 to 59. The age-specific annual incidence rates and penetrance estimate were compared with published figures for women from North America and from Poland. The risk of breast cancer to age 70 was estimated to be 61% for women from Norway, compared with 55% for women from Poland and 69% for women from North America.
La population québécoise (~7 millions d'habitants) est constituée d'environ six millions d'individus descendant d'un bassin génétique estimé à 8500 fondateurs. Les caractéristiques uniques de cette population facilitent beaucoup les recherches en génétique. Cette thèse de doctorat traite de la génétique moléculaire du glaucome, une maladie oculaire insidieuse qui est l'une des principales causes de cécité à travers le monde. Dans le but d'investiguer les facteurs génétiques impliqués dans cette maladie, nous avons recruté des familles ségréguant le glaucome primaire à angle ouvert (GPAO) et des individus non reliés également atteints de glaucome ou d'hyperpression intraoculaire (HTO). Des mutations du ± trabecular meshwork inducible glucocorticoid response gene (TIGR), ou myociline (MYOC), ont été recherchées parmi 18 familles, représentant 180 individus atteints, et 422 cas sporadiques. La prévalence de mutation de ce gène a été établie à 22,2 et 3,8%, respectivement chez les familles et patients non reliés. Des corrélations génotype/phénotype des mutations identifiées ont été établies. Grâce à la détermination de signatures alléliques entourant le gène TIGR/MYOC, il a été possible d'estimer le nombre de fondateurs ayant contribué à la présence des mutations disséminées dans l'échantillon de la population québécoise testée. Huit familles comportant un nombre suffisant d'individus pour la réalisation d'une étude préliminaire de liaison (linkage) ont été génotypées sur six régions de susceptibilité au glaucome déjà rapportées. Le génotypage de ces familles visait la réduction d'intervalles génétiques associés au glaucome dans le but de découvrir d'autres gène responsables de la maladie. Une famille, représentant un potentiel de liaison intéressant au locus GLC1B, a été élargie dans le but d'augmenter le nombre d'individus atteints possédant un haplotype lié à cette région située sur le chromosome 2cen-q13. Malgré l'identification de gènes candidats intéressants dans ce locus, la saturation de la région chromosomique en marqueurs génotypés chez cette famille a révélé l'absence d'un haplotype commun parmi tous les individus affectés. Le recrutement additionnel de larges familles ségréguant le GPAO et l'élargissement de certains pedigrees déjà prélevés seront nécessaires à l'identification de nouveaux facteurs génétiques jouant un rôle important dans cette pathologie oculaire commune. Titre de l'écran-titre (visionné le 22 mars 2004). Thèse (Ph.D.)--Université Laval, 2003. Bibliogr. Disponible en formats XHTML et PDF.
Modifying factors might theoretically determine whether a BRCA1 mutation carrier contracts breast or ovarian cancer. If so, one would expect concordance for breast or ovarian cancer in affected sibships. We identified 64 pairs with cancers where one or both sisters were demonstrated to carry a BRCA1 mutation, and 116 additional constructed pairs in sibships with three or more affected sisters. We analysed concordance for breast and for ovarian cancer both in the complete series and in the 64 sister pairs alone. The results were that concordance for both breast and ovarian cancer in sisters was in keeping with random distribution or multiple and frequent modifying genetic factors. In conclusion, there may be no major modifying factor of expression of BRCA1 mutations. The practical implication of our findings is that previous disease manifestations in close relatives may have no bearing on the first cancer to be expected in a young female mutation carrier.
Inherited ovarian cancer carries a serious prognosis. Prophylactic oophorectomy has been advocated. The degree to which inherited ovarian cancer is restricted to BRCA mutation carriers is not fully known. We wanted to determine the prevalence of BRCA mutation carriers in women at high risk from ovarian cancer.
Healthy women who were found to be at increased risk judged by family history were followed prospectively. Full BRCA1/2 mutation analysis was conducted on all patients who contracted pelvic cancer.
We identified 1,582 women at risk during 5,674 person-years. Forty infiltrating epithelial ovarian cancers, six peritoneal cancers, and one fallopian tube cancer were diagnosed. All but one of these patients (98%) had a BRCA mutation, a frequency that was significantly higher than for the 3 patients with borderline ovarian cancers, who were all mutation negative (P = 0.0002). Eighty-two percent of the detected mutations belonged to one of the 10 Norwegian founder mutations previously reported. At prophylactic bilateral salpingo-oophorectomy, cancer was found in 18 of 345 (5.2%) of mutation carriers compared with none in the 446 mutation negative (P = 0.0000).
In healthy women with a family history of ovarian cancer, high risk for ovarian cancer was restricted to BRCA1/2 mutation carriers. A woman at risk for ovarian cancer according to her family history should have access to full BRCA1/2 mutation testing before deciding on prophylactic bilateral salpingo-oophorectomy.
We aimed to describe the penetrances of the four Norwegian founder mutations in BRCA1 (816delGT, 1135insA, 1675delA and 3347delAG) with regard to breast and ovarian cancers in families ascertained through cancer family clinics or a consecutive series of women with breast or ovarian cancer. We have extended the families as far as possible and tested all family members that asked for genetic testing. Penetrance is based upon counting the mutation carriers. The series contains sufficient numbers of mutation carriers to minimise variation in the estimates due to a limited sample set. The penetrances for all four mutations were high, both with respect to breast and ovarian cancers. This is in accordance with other reports from cancer family clinics, but contrasts with reports from population-based series of mutation carriers. Risks of first cancer (breast or ovarian), breast cancer, and ovarian cancer at age 50 years were 43, 30 and 17%, respectively. Corresponding risks at age 70 years were 84, 58 and 58%. Risks for breast cancer before age 30 years and for ovarian cancer before 35 years were low. Penetrances with regard to ovarian cancer were different for the four mutations. The risk of ovarian cancer was doubled in carriers of the 1675delA mutation when compared with the 816delGT mutation (24 versus 12% at age 50 years, P=0.004). The mutations analysed are high penetrance alleles. No differences in penetrance between the series ascertained through the cancer family clinic or the series of consecutive cancer patients was observed. There are discrepancies between our findings and the low penetrances reported for other mutations in other populations. This may be due to methodological differences, but may reflect differences between mutations and/or modifying factors in different populations.
This study was undertaken to examine transmission of information to first-degree relatives of BRCA1 mutation carriers and uptake of genetic testing. The intention was to consider revision of current legislation related to privacy if information on life-saving health care was not disseminated to at-risk family members. The Norwegian Radium Hospital provides clinical genetics services for families at high risk for hereditary breast and ovarian cancer. Together with major hospitals nationwide we provide medical surveillance. Nearly all expenses are covered by the National Health insurance. Because of the high number of families with founder mutations in BRCA1, we are in a unique position to gather information about these groups. Within a consecutive series, we identified 75 BRCA1 mutation carriers and registered information transmission and uptake of genetic testing 6 months or more after the index mutation carriers had been informed about their mutation status. These 75 BRCA1 mutation carriers had 172 living first-degree relatives, aged 18 years or older (84 females, 88 males). Forty-four out of 54 (81.5%) of females over 30 had opted for genetic testing. The testing rate among all relatives was 43%. At any age, 63 % of the females underwent genetic testing compared with 24% of the males (p<0.05%). The overwhelming majority of adult females at risk opted for genetic testing. Males with daughters more frequently than males without daughters asked for testing. The findings give neither reason to reconsider legislation on privacy, nor for us to consider more aggressive methods of contacting relatives.
A group of 63 families from the Pomerania-Kujawy region were analyzed for three BRCA1 gene Polish founder mutations, 5382insC, 300T>G, and 4153delA, because of breast (BrCa) and/or ovarian cancer (OvCa) history. The analysis was carried out by multiplex polymerase chain reaction method. BRCA1 mutation was revealed in nine (14%) families: in three (33%) of hereditary BrCa and OvCa families, in three (8%) of hereditary BrCa families, and in three (21%) of hereditary OvCa families. According to risk criteria, it was revealed in 45% of high-risk families with more than three cancers, 13% of moderate-risk families with two cancers, and 8% of families with sporadic OvCa. In six families, the mutation was found in a proband with BrCa or OvCa and in three families, the mutation was found in a healthy proband, first-degree relative of a patient deceased of BrCa or OvCa. 5382insC frameshift mutation accounted for 67% and 300T>G missense mutation for 33% of all identified familial mutations. 4153delA frameshift mutation was not found in analyzed sample of families. 5382insC mutation was found in 9% and 300T>G in 5% of all investigated families, and in 27 and 18%, respectively, of high-risk families. This underlines the importance of applying strict inclusion criteria to analyze mutation frequency in hereditary BrCa/OvCa families.
To examine the short-term psychological impact of receiving definite results concerning BRCA1 mutation status in a clinical setting.
A test was offered for consecutive sample of 395 women from 53 families with demonstrated BRCA1 mutations. The sample included 50 women with a personal history of cancer, and 345 women without. Of the 287 women who chose to be tested and participated in the study, 79% of those with cancer 33% of those without cancer had a demonstrated BRCA1 mutation. Psychological distress was measured with the hospital anxiety and depression scale (HADS), the general health questionnaire (GHQ-28), the impact of event scale (IES) and Beck's hopelessness scale (BHS) at the time the patients were offered testing and six weeks after receiving the test result.
No significant changes were found in psychological distress from baseline to follow-up in any groups. Women with cancer were significantly more distressed than those without both at baseline and at six weeks, while women without cancer had levels of psychological distress comparable to or lower than normative data as measured by HADS.
Our sample had a low level of psychological distress at baseline. Receiving a definite positive or negative result on the BRCA1 test had minimal effects on short-term psychological distress. These findings indicate that establishing a special psychological service in relation to predictive BRCA1 testing could be superfluous.
The aims of the present study were to find the frequency of the most common BRCA1 mutations in women with ovarian tumours identified from a population-based cancer registry and in the general population, to estimate the relative risk of ovarian tumours among the mutation carriers, and to explore the value of using CA125 as a prediagnostic test. The study was designed as a nested case-control study within a cohort mainly consisting of participants in population-based health examinations. The data files of The Cancer Registry of Norway and the Janus serum bank were linked to identify cases with ovarian cancer and borderline tumours. Hereditary BRCA1 mutations were determined using archived serum samples and capillary electrophoresis. Altogether 478 ovarian cancer patients and 190 patients with borderline tumours were identified, and 1421 and 568 matching controls were selected. Odds ratios (OR) of developing ovarian cancer and borderline tumours in the presence of BRCA1 mutations and CA125 level were derived from conditional logistic regression models. Among the 478 ovarian cancer patients, 19 BRCA1 mutations were identified (1675delA, 1135insA, 816delGT and 3347delAG), none among the patients with borderline tumours. Only two of the 1989 controls were BRCA1 mutation carriers (0.10%). The risk of ovarian cancer among the mutation carriers was strongly elevated (OR=29, 95% CI=6.6-120). CA125 was a marker for ovarian cancer, but the sensitivity was low. This study showed that BRCA1 mutation carriers have a very high risk of ovarian cancer. However, since the prevalence of BRCA1 mutations in the Norwegian population was low, the proportion of ovarian cancers due to BRCA1 mutations seemed to be low, about 4%. The sensitivity of using CA125 only as a screening test for ovarian cancer was low.
The aim of the study was to estimate the prevalence of hereditary cancers and the need for surveillance in Telemark county, Norway.
All persons attending the Norwegian Colorectal Cancer Prevention (NORCCAP) trial in Telemark were interviewed about cases of cancer in the family. Diagnoses were verified, pedigrees constructed and families classified according to preset criteria aiming at identifying hereditary cancer. Mutation analyses were performed in kindreds at risk for breast cancers when possible. Immunohistochemistry of tumors in assumed inherited colorectal cancer families was undertaken.
The screening examination was attended by 7,224 persons among whom 2,866 had cancer in the family. Of these, 2,479 had no suspicion of any known inherited cancer syndrome. Family information questionnaires were mailed to 387 persons and returned by 191. Sixty-four of these 191 met the clinical criteria for familial cancer by family history after verification of diagnoses. Observed prevalences for being at risk for hereditary breast and breast-ovarian cancer (HBOC) or hereditary non-polyposis colorectal cancer (HNPCC) were 2.8 per thousand and 0.77 per thousand, respectively.
The number of colonoscopies and mammograms obtained per year serving those who needed them was limited and reduced by clinical genetic work-up from 2,866 with a family history of cancer to 64 proven cases. Continued surveillance of an unnecessarily high number leads to unjustified cancer worry, is costly and uses up health-care facilities. Genetic work-up is a one-time job that reduces input numbers to surveillance programs, provides a starting-point for mutation testing and is economically cost beneficial if inherited cancers are prevented or cured by the health-care programs offered.
There is increasing evidence that hereditary factors play a greater role in ovarian cancer than in any of the other common cancers of adulthood. This is attributable, to a large extent, to a high frequency of mutations in the BRCA1 or BRCA2 genes. In Poland, 3 common founder mutations in BRCA1 account for the majority of families with identified BRCA mutations. Our study was conducted in order to estimate the prevalence of any of 3 founder BRCA1 mutations (5382insC, C61G and 4153delA) in 364 unselected women with ovarian cancer, and among 177 women with ovarian cancer and a family history of breast or ovarian cancer. A mutation was identified in 49 out of 364 unselected women with ovarian cancer (13.5%) and in 58 of 177 women with familial ovarian cancer (32.8%). The majority of women with ovarian cancer and a BRCA1 mutation have no family history of breast or ovarian cancer. The high frequency of BRCA1 mutations in Polish women with ovarian cancer supports the recommendation that all Polish women with ovarian cancer should be offered testing for genetic susceptibility, and that counseling services be made available to them and to their relatives. It is important that mutation surveys be conducted in other countries prior to the introduction of national genetic screening programs.
Ten BRCA mutations were demonstrated to be frequent in the Norwegian population. We present maps verifying the uneven distribution of prevalences according to municipality. We tested incident breast cancer cases treated in Mid-Norway from 1999 onwards for these mutations. Uptake of testing was 97% and 2.5% were demonstrated to be mutation carriers. Ten (77%) were outside families previously known to carry a mutation. Ten (77%) did not meet clinical criteria to be selected for mutation testing. We tested incident ovarian cancer cases in South-West Norway from 2001 onwards. Uptake of testing was 80% and 23% were mutation carriers. Twenty-one (88%) were outside families previously known. Twelve (67%) did not meet clinical criteria to be selected for testing. All patients with mutation collaborated actively to give our offer of predictive genetic testing to their relatives. No complaint on the activity was received.
Estimates of the contribution of BRCA1 and BRCA2 to breast cancer incidence in outbred populations have been based on studies that are either small or have selected for cases diagnosed at an early age. Only one of these has reported an estimate of the breast cancer risk associated with a mutation in these genes, and there is no published ovarian cancer risk estimate derived from a population-based case series. We screened a population-based series of breast cancer cases diagnosed before the age of 55 for mutations in BRCA1 and BRCA2. Pedigree information from the mutation carriers was used to estimate penetrance and the proportion of familial risk of breast cancer due to BRCA1 and BRCA2. We identified eight (0.7%) BRCA1 and 16 (1.3%) BRCA2 mutation carriers in 1220 breast cancer cases (actual sample size 1435 adjusted for 15% polymerase chain reaction failure rate). Mutation prevalence was substantially higher in cases diagnosed before 35 years-of-age and with increasing number of relatives affected with breast or ovarian cancer. However, most mutation carriers were diagnosed in the older age groups, and a minority reported a first-degree relative with breast cancer. Breast cancer penetrance by age 80 was estimated to be 48% (95% CI 7–82%) for BRCA1 mutation carriers and 74% (7–94%) for BRCA2 mutation carriers. Ovarian cancer penetrance for BRCA1 and BRCA2 combined was 22% (6–65%) by age 80. 17% of the familial risk of breast cancer was attributable to BRCA1 and BRCA2. At birth, the estimated prevalence of BRCA1 mutation carriers was 0.07% or 0.09% depending on the penetrance function used for the calculation. For BRCA2 the birth prevalence estimates were 0.14% and 0.22%. Mutations in the genes BRCA1 and BRCA2 are rare in the population and account for a small fraction of all breast cancer in the UK. They account for less than one fifth of the familial risk of breast cancer. Eligibility criteria for BRCA1 and BRCA2 mutation testing based on family history and age of onset will identify only a small proportion of mutation carriers. © 2000 Cancer Research Campaign
Since BRCA1, the first major gene responsible for inherited breast cancer, was cloned, more than 50 unique mutations have been detected in the germline of individuals with breast and ovarian cancer. In high-risk pedigrees, female carriers of BRCA1 mutations have an 80-90% lifetime risk of breast cancer, and a 40-50% risk of ovarian cancer. However, the mutation stats of individuals unselected for breast or ovarian cancer has not been determined, and it is not known whether mutations in such individuals confer the same risk of cancer as in individuals from the high-risk families studied so far. Following the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families, we have determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference individuals not selected for ethnic origin. We observed the 185delAG mutation in 0.9% of Ashkenazim (95% confidence limit, 0.4-1.8%) and in none of the reference samples. Our results suggest that one in a hundred women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer.
A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, θ = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
Human breast cancer is usually caused by genetic alterations of somatic cells of the breast, but occasionally, susceptibility to the disease is inherited. Mapping the genes responsible for inherited breast cancer may also allow the identification of early lesions that are critical for the development of breast cancer in the general population. Chromosome 17q21 appears to be the locale of a gene for inherited susceptibility to breast cancer in families with early-onset disease. Genetic analysis yields a lod score (logarithm of the likelihood ratio for linkage) of 5.98 for linkage of breast cancer susceptibility to D17S74 in early-onset families and negative lod scores in families with late-onset disease. Likelihood ratios in favor of linkage heterogeneity among families ranged between 2000:1 and greater than 10(6):1 on the basis of multipoint analysis of four loci in the region.
A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified
by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate
BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense
substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary,
and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region,
but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of
breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.
Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.
Studies on Icelandic breast cancer families have shown that most of them segregate a 999del5 BRCA2 mutation. Here, we report the frequency of the 999del5 BRCA2 mutation in an Icelandic control population and four different groups of cancer patients diagnosed with (a) breast cancer; (b) ovarian cancer; (c) prostate cancer (patients younger than 65 years); and (d) other cancer types. The proportions of individuals carrying the mutation were 0.4% in the control population and in the patient groups 8.5%, 7.9%, 2.7%, and 1.0%, respectively. Our results indicate that BRCA2 confers a very high risk of breast cancer and is responsible for a substantial fraction of breast and ovarian cancer in Iceland, but only a small proportion of other cancers.
One hundred breast and breast-ovarian cancer families identified at the Helsinki University Central Hospital in southern Finland and previously screened for mutations in the BRCA2 gene were now analyzed for mutations in the BRCA1 gene. The coding region and splice boundaries of BRCA1 were analyzed by protein truncation test (PTT) and heteroduplex analysis (HA)/SSCP in all 100 families, and 70 were also screened by direct sequencing. Contrary to expectations based on Finnish population history and strong founder effects in several monogenic diseases in Finland, a wide spectrum of BRCA1 and BRCA2 mutations was found. In the BRCA1 gene, 10 different protein truncating mutations were found each in one family. Six of these are novel Finnish mutations and four have been previously found in other European populations. Six different BRCA2 mutations were found in 11 families. Altogether only 21% of the breast cancer families were accounted for by mutations in these two genes. Linkage to both chromosome 17q21 (BRCA1) and 13q12 (BRCA2) was also excluded in a subset of seven mutation-negative families with four or more cases of breast or ovarian cancer. These data indicate that additional breast and breast-ovarian cancer susceptibility genes are likely to be important in Finland.
PTEN, a protein tyrosine phosphatase with homology to tensin, is a tumor-suppressor gene on chromosome 10q23. Somatic mutations in PTEN occur in multiple tumors, most markedly glioblastomas. Germ-line mutations in PTEN are responsible for Cowden disease (CD), a rare autosomal dominant multiple-hamartoma syndrome. PTEN was sequenced from constitutional DNA from 25 families. Germ-line PTEN mutations were detected in all of five families with both breast cancer and CD, in one family with juvenile polyposis syndrome, and in one of four families with breast and thyroid tumors. In this last case, signs of CD were subtle and were diagnosed only in the context of mutation analysis. PTEN mutations were not detected in 13 families at high risk of breast and/or ovarian cancer. No PTEN-coding-sequence polymorphisms were detected in 70 independent chromosomes. Seven PTEN germ-line mutations occurred, five nonsense and two missense mutations, in six of nine PTEN exons. The wild-type PTEN allele was lost from renal, uterine, breast, and thyroid tumors from a single patient. Loss of PTEN expression was an early event, reflected in loss of the wild-type allele in DNA from normal tissue adjacent to the breast and thyroid tumors. In RNA from normal tissues from three families, mutant transcripts appeared unstable. Germ-line PTEN mutations predispose to breast cancer in association with CD, although the signs of CD may be subtle.
The majority of breast cancer in high risk families is believed to result from a mutation in either of two genes named BRCA1 and BRCA2. A germline defect in either gene is usually followed by chromosomal deletion of the normal allele in the tumour. In Iceland two recurrent mutations have been identified, 999del5 BRCA2 and G5193A BRCA1. In this study, randomly selected pairs of sisters diagnosed with breast cancer at the age of 60 years or younger were analysed to evaluate the proportion of breast cancer resulting from BRCA1 and BRCA2. Genotypes and allele loss in tumour tissue from 42 sister pairs were compared using markers within and around the BRCA1 and BRCA2 genes. Eleven sister pairs were highly suggestive of BRCA2 linkage, and no obvious BRCA1 linkage was seen. Screening for the G5193A BRCA1 and 999del5 BRCA2 mutations showed the 999del5 mutation in the 11 BRCA2 suggestive pairs plus three pairs less indicative of linkage, and the G5193A BRCA1 mutation in one pair. When known mutation carriers are removed from the group, no indication of further linkage to BRCA1 or BRCA2 is seen. The results of our studies suggest that a large proportion of familial breast cancer in Iceland is the result of the 999del5 BRCA2 mutation, and it is unlikely that BRCA1 and BRCA2 germline mutations other than 999del5 and G5193A play a significant role in hereditary breast cancer in Iceland. Furthermore it can be concluded that most families with BRCA1 or BRCA2 linkage are easily identified by studying LOH around the defective gene in as few as two affected relatives.
Based on results from our surveillance program for women at risk for inherited breast cancer, we have calculated cost per year earned. Norwegian National Insurance Service reimbursement fees were used in the calculations. The calculated costs are based on empirical figures for expanding already established medical genetic departments and diagnostic outpatient clinics to undertake the work described. Cost per year earned was estimated at Euro 753 using our current practice of identifying the high-risk women through a traditional cancer family clinic.
A strategy of identifying the high-risk families through genetic testing of all incident breast and ovarian cancers for founder mutations in BRCA1, will increase the cost to Euro 832. Costs related more to genetic counseling and clinical follow-up than to laboratory procedures. This potential economic limiting factor coincides with a shortage of personnel trained in genetic counseling. The number of relatives counseled to identify one healthy female mutation carrier (i.e. the uptake of genetic testing) is more important to cost-effectiveness than family size. Costs will vary depending upon the penetrance of the mutations detected and the prevalence of founder mutations in the population examined. Prevalences of BRCA1 founder mutations in some high incidence areas of Norway may be sufficiently high to consider population screening. Unlike mutation screening of cancer genes, founder mutation analysis will not identify DNA variants of uncertain clinical significance. Identification of high-risk families through founder mutation analysis of BRCA1 ensures that families with maximum risks are given first access to the limited resources of the high-risk clinics. This may be the greatest contribution to increased cost effectiveness of such a strategy.
The assumptions underlying the calculations are discussed. The conclusion is that inherited breast cancer may be managed effectively for the cost of Euro 750–1,600 per year earned.
232 family members from 27 Norwegian families with BRCAl mutations were offered genetic testing. 180/232 (78%) chose to be tested, 14/232 (6%) have not yet decided and 38/232 (16%) declined. All 232 persons were invited to fill in the following questionnaires when offered testing: Impact of Event Scale (IES), Hospital Anxiety and Depression Scale (HADS), General Health Questionnaire (GHQ-28) and Beck Hopelessness Scale (BHS). 207/232 (89%) responded to the questionnaires. Of those declining to be tested 23/38 (61%) answered the questionnaires compared to 170/180 (94%) of those wanting the test (p < 0.0001).
A higher proportion of females with a history of cancer than females without such a history had abnormal scores on the IES-intrusion and GHQ questionnaires (p < 0.001). Healthy females who were deciding on predictive testing had the same or lower prevalence of mental distress compared to the general population, between 4.3% and 18.0% as measured by the different questionnaires. Males did not differ from healthy females on any of the measures.
According to their HADS scores, women without a history of cancer deciding on predictive testing for breast-ovarian cancer had lower or equal levels of mental distress compared to the general population. The high uptake of genetic testing combined with the lower than normal prevalence of mental distress indicates that the activity may continue as practised, awaiting longitudinal data concerning the levels of mental distress after genetic testing.
A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
In Western Europe and the United States approximately 1 in 12 women develop breast cancer. A small proportion of breast cancer cases, in particular those arising at a young age, are attributable to a highly penetrant, autosomal dominant predisposition to the disease. The breast cancer susceptibility gene, BRCA2, was recently localized to chromosome 13q12-q13. Here we report the identification of a gene in which we have detected six different germline mutations in breast cancer families that are likely to be due to BRCA2. Each mutation causes serious disruption to the open reading frame of the transcriptional unit. The results indicate that this is the BRCA2 gene.
In Western Europe and the United States approximately 1 in 12 women develop breast cancer. A small proportion of breast cancer cases, in particular those arising at a young age, are attributable to a highly penetrant, autosomal dominant predisposition to the disease. The breast cancer susceptibility gene, BRCA2, was recently localized to chromosome 13q12-q13. Here we report the identification of a gene in which we have detected six different germline mutations in breast cancer families that are likely to be due to BRCA2. Each mutation causes serious disruption to the open reading frame of the transcriptional unit. The results indicate that this is the BRCA2 gene.
Iselius L, Littler M, Morton N. Transmission of breast cancer - a controversy resolved. Clin Genet 1992:41: 211–217.
The Danish breast cancer data collected by Jacobsen (1946) have been reanalysed using morbid risks which incorporate mortality due to breast cancer. A dominant gene is favoured for familial breast cancer, supporting the conclusions of Williams & Anderson (1984) and later authors. Neglect of specific mortality does not greatly alter estimates of gene frequency and displacement, but the evidence for a major gene is inflated. No evidence for heterogeneity was found. Earlier claims of non-Mendelian transmission are in error since we have discovered that transmission probabilities are not correctly implemented in the computer program POINTER. Cases with bilateral breast cancer and males with breast cancer all belonged to families favouring a major gene. Of the cancer sites frequently reported to be associated with familial breast cancer, only ovarian cancer is significant in this material.
Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly
inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that
occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach
was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications
that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line
p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein
expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations
can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that
might be attributed to the mutation.
RFLPs in the phenylalanine hydroxylase (PAH) gene locus were determined in 47 Norwegian nuclear families that had at least one child with phenylketonuria (PKU). The PKU haplotype distribution differed somewhat from that of other European populations. Mutant haplotype 7 is relatively rare in other populations but constituted 20% of all mutant haplotypes in Norway. In 14 of the 17 mutant haplotypes 7, a previously unreported deletion of the BamHI restriction site in exon 7 of the PAH gene was observed. The abrogation of the BamHI site was shown to be due to a G-to-T transversion, changing Gly 272 to Ter 272 in exon 7 of the gene, thus directly identifying the PKU mutation. Unlike the families of the other PKU patients, the families with this mutation clustered along the southeastern coast of Norway, suggesting a founder effect for this mutation.
A small proportion of breast cancer, in particular those cases arising at a young age, is due to the inheritance of dominant susceptibility genes conferring a high risk of the disease. A genomic linkage search was performed with 15 high-risk breast cancer families that were unlinked to the BRCA1 locus on chromosome 17q21. This analysis localized a second breast cancer susceptibility locus, BRCA2, to a 6-centimorgan interval on chromosome 13q12-13. Preliminary evidence suggests that BRCA2 confers a high risk of breast cancer but, unlike BRCA1, does not confer a substantially elevated risk of ovarian cancer.
Previous studies of high-risk breast cancer families have proposed that two major breast cancer-susceptibility genes, BRCA1 and BRCA2, may account for at least two-thirds of all hereditary breast cancer. We have screened index cases from 106 Scandinavian (mainly southern Swedish) breast cancer and breast-ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using the protein-truncation test, SSCP analysis, or direct sequencing. A total of 24 families exhibited 11 different BRCA1 mutations, whereas 11 different BRCA2 mutations were detected in 12 families, of which 3 contained cases of male breast cancer. One BRCA2 mutation, 4486delG, was found in two families of the present study and, in a separate study, also in breast tumors from three unrelated males with unknown family history, suggesting that at least one BRCA2 founder mutation exists in the Scandinavian population. We report 1 novel BRCA1 mutation, eight additional cases of 4 BRCA1 mutations described elsewhere, and 11 novel BRCA2 mutations (9 frameshift deletions and 2 nonsense mutations), of which all are predicted to cause premature truncation of the translated products. The relatively low frequency of BRCA1 and BRCA2 mutations in the present study could be explained by insufficient screening sensitivity to the location of mutations in uncharacterized regulatory regions, the analysis of phenocopies, or, most likely, within predisposed families, additional uncharacterized BRCA genes.
We searched for a founder mutation in a population from one geographic region of Norway with prevalent breast/ovarian cancer families. We sampled 33 breast/ovarian cancer families and determined haplotypes of four markers linked to the BRCA1 region. Of the affected 33 index women, 13 (39.4%) shared one haplotype. In five (15% of total), an identical mutation was indicated by an abnormal truncated protein test (PTT) of exon 11 and shown to represent a 1675delA mutation. In the other index women, PTT of exon 11 showed no abnormality. No other BRCA1 founder mutation of this prevalence is likely because no other haplotype was more frequent in affecteds than in controls. All families with the 1675delA mutation in this geographic region may be considered as part of one large kindred. This allows a genotype-phenotype correlation to be precisely determined and used in genetic counselling for predictive testing within this kindred. Identification of identical haplotypes between unrelated affected individuals may be used to estimate the extent of founder effects for any mapped disease, without knowledge of the specific founder mutation.
Our aim was to determine the prevalence of two Norwegian BRCA1 founder mutations in ovarian cancer patients, to identify carriers and their families for medical follow-up, and to study histopathological factors. Of a cohort of 727 ovarian cancer patients, 615 gave informed consent to testing. 2.9% (18/615) of the tested patients were found to be carriers of BRCA1 1675delA (n = 13) or 1135insA (n = 5). The total frequency of the mutations was 4.7% (8/171) in patients below 50 years of age, and zero (0/144) in patients above 70 years of age. In patients below 70 years of age, the frequency of 1675delA and 1135insA mutations was 2.8% and 1.0%, respectively. Out of 13 patients with 1675delA mutation, 4 had breast cancer. 14/16 (87.5%) families fulfilled clinical criteria for familial breast-ovarian cancer. Median age of onset of ovarian and breast cancer was 51 years and 37 years, respectively. Mutation carriers tended to have tumours with unfavourable prognostic factors. This is, to our knowledge, the highest reported frequency of founder mutations in a national ovarian cancer cohort (less than in the Ashkenazis). It seems justified to offer such testing to ovarian cancer patients below 70 years of age in Norway, identify their risk of breast cancer and offer medical follow-up to the families.
Inherited breast cancer is a heterogenous group of diseases. We examined this heterogeneity in a prospective series of inherited breast and ovarian cancers, previously demonstrated to include 84% of inherited cancers. Ninety-two tumours (65 breast and 27 ovarian) in 82 patients from 70 kindreds were prospectively diagnosed. Fifteen of the breast cancers were in situ, 50 were infiltrating. 40 (49%) of the 82 women carried a BRCA1 mutation, whereas no mutation in BRCA2 was found. Approximately, two-thirds of the BRCA1 mutation carriers had one of the four most frequent Norwegian founder mutations. Ninety-five per cent of the epithelial ovarian cancers occurred in BRCA1 mutation carrying women versus 38% of infiltrating breast cancers and 7% of carcinoma in situ of the breast. The BRCA1 syndrome was phenotypically distinct with invasive, high grade, oestrogen receptor-negative breast cancers and epithelial ovarian cancers. Non-BRCA1/2 inherited breast cancers included carcinoma in situ and lobular carcinoma and were frequently bilateral. Non-BRCA1/2 inherited breast cancer is not associated with epithelial ovarian cancer and in breast cancers has distinct biological characteristics, indicating that the different subgroups of inherited breast cancer may need different healthcare services.
Sogn og Fjordane Central Hospital, Førde)
- S Haram
S. Haram (Sogn og Fjordane Central Hospital, Førde);
Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neo-plasms
- Li D Fp Malkin
- Strong
- Lc
Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neo-plasms. Science 1990, 250, 1233–1238.
Hospital of Gjø-vik, Gjøvik)
- S Døssland
S. Døssland (Hospital of Gjø-vik, Gjøvik);
Hospital of Ham-merfest, Hammerfest)
- S Hammelbo
S. Hammelbo (Hospital of Ham-merfest, Hammerfest);
Zeitschrift fu¨r Mun-dartforschung
- I Hoff
- Norwegische
- Mundartforschung
Hoff I. Norwegische Mundartforschung. Zeitschrift fu¨r Mun-dartforschung 1970, 6, 399–458.
The Regional Hos-pital, Trondheim)
- H E Fjøsne
H.E. Fjøsne (The Regional Hos-pital, Trondheim);
The Regional Hospital, Tromsø); S. Hammelbo (Hospital of Hammerfest , Hammerfest); K. Raanes and C
- J Due
- A Himmelmann
- A F Rosenlund
J. Due,
A. Himmelmann and A.F. Rosenlund (The Regional
Hospital, Tromsø); S. Hammelbo (Hospital of Hammerfest, Hammerfest); K. Raanes and C.CH. Verhage
(Hospital of Harstad, Harstad).
Jenssen (Hospital of Innherred, Levanger); H.E. Fjøsne (The Regional Hospital , Trondheim)
- M Saevik Lode
M. Saevik Lode (Møre og Romsdal
Central Hospital, A ˚ lesund); T.A. Jenssen (Hospital of
Innherred, Levanger); H.E. Fjøsne (The Regional Hospital, Trondheim); G.A. Rønning, A. Schifloe and H.
Wasmuth (Nordland Central Hospital, Bodø);
Vest-Agder Central Hospital , Kristiansand)
- I Fjaerestad
- E Stenehjem
I.
Fjaerestad and E. Stenehjem (Vest-Agder Central Hospital, Kristiansand); A.H. Liava˚gLiava˚g, S. Mathisen and S.
Svenningsen (Aust-Agder Central Hospital, Arendal);
Appendix Additional members of The Norwegian Inherited Breast Cancer Group and The Norwegian Inherited Ovarian Cancer GroupThe Norwegian Radium Hospital, Oslo)
- H Bjørndal
- P Bøhler
- A Dørum
- K-E Giercksky
- P Helgerud
- L Hansen
- G Kristensen
- C Tropeánd
- H Qvist
- T Aas
- L F Engebretsen
- R Sandvei
- J E Varhaug
Appendix
Additional members of The Norwegian Inherited Breast
Cancer Group and The Norwegian Inherited Ovarian
Cancer Group, are: H. Bjørndal, P. Bøhler, A. Dørum,
K-E. Giercksky, P. Helgerud, L. Jul Hansen, G. Kristensen, C. Tropeánd H. Qvist (The Norwegian Radium
Hospital, Oslo); T. Aas, L.F. Engebretsen, R. Sandvei,
and J.E. Varhaug (Haukeland University Hospital,
Bergen); S. Haram (Sogn og Fjordane Central Hospital,
Førde);
Søreide (Rogaland Central Hospital, Stavanger); H. Espelid and S.I. Lie (Hospital of Haugesund
- A Løvslett
- J A Nysted
Løvslett, A. Nysted and J.A. Søreide (Rogaland Central
Hospital, Stavanger); H. Espelid and S.I. Lie (Hospital
of Haugesund, Haugesund);
Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms
- Malkin
A population study of mutations and LOH at breast cancer gene loci in tumours from sister pairs
- Arason