<i>BRCA1</i> and<i>BRCA2</i> mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age

Bergþórsson, Jón Þór; Ejlertsen, Bent; Olsen, Jørgen H.; Borg, Åke; Nielsen, Kirsten; Barkardóttir, Rósa B.; Klausen, Siri; Mouridsen, Henning T.; Winther, Kaj; Fenger, Kirsten; Niebuhr, Anita; Harboe, Theresa Larriba; Niebuhr, Erik

doi:10.1136/jmg.38.6.361

Cited by 45 publications

(37 citation statements)

References 29 publications

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“…The literature is not unanimous about the predictive value of multiple primary (ipsilateral or contralateral) breast cancers for finding a mutation. Our results are in agreement with the studies of Bergthorsson et al (2001), de la Hoya et al (2002 and Ford et al (1998); however, others failed to demonstrate such a predictive value (Couch et al, 1997;Steinmann et al, 2001). Male breast cancer in combination with a family history of breast/ovarian cancer was indicative of finding a BRCA2 mutation (P ¼ 0.002), which is consistent with a recent population-based British study (Basham et al, 2002).…”

Section: Discussionsupporting

confidence: 93%

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

et al. 2004

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Worldwide variation in the distribution of BRCA1 and BRCA2 mutations is well recognised, and for the Belgian population no comprehensive studies about BRCA1/2 mutation spectra or frequencies have been published. We screened the complete coding region of both genes in 451 individuals from 349 Belgian families referred to a family cancer clinic and identified 49 families with a BRCA1 and 26 families with a BRCA2 mutation. Six major recurrent mutations (BRCA1 IVS5 þ 3A4G, 2478 -2479insG, E1221X and BRCA2 IVS6 þ 1G4A, 6503-6504delTT, 9132delC) accounted for nearly 60% of all mutations identified. Besides 75 true pathogenic mutations, we identified several variants of unknown clinical significance. In combination with a family history, an early average age of female breast cancer diagnosis (Po0.001), and the presence of a relative with ovarian cancer (Po0.0001) or multiple primary breast cancers (P ¼ 0.002), increased the chance for finding a mutation. Male breast cancer was indicative of a BRCA2 mutation segregating in the family (P ¼ 0.002). Mutations in the 5 0 -end of BRCA1 and BRCA2 were associated with a significantly increased risk for ovarian cancer relative to the central portion of the gene. Our study suggests a role for additional breast cancer susceptibility genes in the Belgian population, since mutation detection ratios were low in high-risk breast cancer-only families as compared to breast -ovarian cancer families. Given the large proportion of recurring mutations, molecular testing can now be organised in a more cost-effective way. Our data allow optimisation of genetic counselling and disease prevention in Belgian breast/ovarian cancer families. Since the mapping and the cloning of two genes that confer susceptibility to both breast and ovarian cancer, BRCA1 and BRCA2 (Miki et al, 1994;Wooster et al, 1995;Tavtigian et al, 1996), it became possible to offer genetic testing to families with a predisposition for breast and/or ovarian cancer. Consequently, individuals at risk can now be identified as candidates for surveillance programmes. A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but population-specific variation in the distribution of BRCA1/2 mutations is well recognised. In some populations or ethnic groups, founder mutations form a sufficient proportion of the total to justify the adoption of specific molecular screening strategies.To date, no comprehensive studies in the Belgian population have been published. Only data from small series are available (Claes et al, 1999a, b) or from studies in which the analysis was restricted to a few BRCA1/2 exons or to BRCA1 only Sibille-Hoang et al, 1998;Goelen et al, 1999). We performed mutation screening of the complete coding region of BRCA1 and BRCA2 in 349 unrelated Belgian families referred to our family cancer clinic and report here the nature and distribution of the mutations identified. We found phenotypic differences between families in whom a disease-causing mutation was identified vs BRCA1/2 muta...

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Section: Discussionsupporting

confidence: 93%

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

et al. 2004

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“…The 5386insC mutation (also known as 5382insC) is common throughout Europe and is also a founder mutation in the Ashkenazi Jewish population. The 2594delC mutation constituted 18% of BRCA1 mutations in this study and was found at a similar frequency (17%) in the study of breast cancer cases from Denmark (20). The 3829delT and Q563X mutations have also been reported in studies from Sweden, suggesting that they may be Swedish/Danish founder mutations.…”

Section: Discussionsupporting

confidence: 52%

“…[13][14][15][16][17][18][19], but the data from the Danish population are much more limited. The largest study of BRCA1 and BRCA2 mutations to date from Denmark is the analysis of 103 multifocal or bilateral early-onset breast cancers, which identified mutations in 20% of cases (20). There are no reports in the literature describing the analysis of BRCA1 and BRCA2 in population-based ovarian cancer cases from Denmark.…”

mentioning

confidence: 99%

BRCA1 and BRCA2 Mutation Prevalence and Clinical Characteristics of a Population-Based Series of Ovarian Cancer Cases from Denmark

Soegaard

Kjær

Cox

et al. 2008

Clinical Cancer Research

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Purpose:To evaluate the prevalence of BRCA1and BRCA2 mutations and associations with clinical correlates of disease in a population-based series of ovarian cancer cases from Denmark. Methods: DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to analyze the BRCA1 and BRCA2 genes for coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer. We evaluated associations between mutation status and clinical characteristics, including cancer risks for first-degree relatives and clinicopathologic features of tumors. Results: Deleterious BRCA1 or BRCA2 mutations were identified in 26 cases; thus, mutations in these genes are responsible for at least 5.8% of ovarian cancer cases in this population. Five different mutations were identified in more than one individual, suggesting that they may be founder mutations in Denmark. We identified several differences between mutation carriers and noncarriers: mutation carriers were diagnosed at a significantly early age (median, 49 and 61 years, respectively; P = 0.0001); the frequency of BRCA1 mutation carriers was 23% for women diagnosed <40 years,15% for 40 to 49 years, 4% for 50 to 59 years, and 2% for z60 years (P = 0.00002); ovarian cancer in carriers was diagnosed at a later stage (P = 0.002) and tumors were of poorer grade (P = 0.0001); and first-degree relatives of mutation carriers had greater relative risks of both ovarian cancer [10.6 (95% confidence interval, 4.2-26.6); P < 0.0001] and breast cancer <60 years [8.7 (95% confidence interval, 3.0-25.0); P < 0.0001].Conclusion: These data may have a significant effect on risk assessment and clinical management of individuals from Denmark who are predisposed to ovarian cancer because they carry a BRCA1 or BRCA2 mutation.

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“…6 Although not highly quantitative, the Breast Cancer Information Core provides a valuable resource for tracking the occurrence of mutations throughout both the BRCA1 and BRCA2 genes. Also observed was a 5301insA change in BRCA2, reported several times in European women (29,31,32) and in women of Near and Middle Eastern descent in the Breast Cancer Information Core.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 and BRCA2 Mutations in Women from Shanghai China

Suter¹,

Ray

et al. 2004

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Little is known about the frequency of germ-line mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 among Asian populations. We investigated the distribution of BRCA1 and BRCA2 germline mutations and polymorphisms in a cohort of women from Shanghai, China.Study subjects totaled 1306, and included 645 women with breast cancer, 342 women with benign breast disease, and 319 unaffected controls, born between 1924 and 1958, selected from women enrolled in a randomized trial of Breast Self-Examination in Shanghai, China. Women were selected without regard to family history of breast or ovarian cancer. All of the coding regions and exon-intron boundaries were screened. Data were analyzed with respect to age at diagnosis, and family history of breast and ovarian cancer.The prevalence of known disease-associated mutations in women with breast cancer was 1.1% each, for BRCA1 and BRCA2. Among breast cancer cases with a family history of breast or ovarian cancer, 8.1% and 2.7% carried likely BRCA1 and BRCA2 disease-associated mutations, respectively.Overall, these results suggest that inherited susceptibility to breast cancer due to germ-line BRCA1/2 mutations among women with a family history of breast cancer is comparable between women from Shanghai and Caucasian women of Western European descent. Most alterations observed appear unique to the Chinese population, suggesting a resource that will be useful for assessing risk among both Chinese women and United States women of Chinese descent. IntroductionAlthough the incidence of breast cancer in China is about one-third that in the United States (1), the overall rate of breast cancer in women from China has been increasing (2). Little is known regarding the role of inherited susceptibility genes in breast cancer risk among Chinese women. To develop genetic screening guidelines for both Chinese women and United States women of Chinese descent, a population-based assessment of BRCA1 and BRCA2 germ-line mutation distribution and frequency is needed.To date, information regarding the frequency of BRCA1 and BRCA2 mutations in Chinese women with breast cancer has been derived from two small hospital-based reports. In the first, 76 consecutive breast cancer cases diagnosed before age 40, and 16 women with a family history of breast or ovarian cancer, were screened for germ-line mutations in BRCA1 (3). Protein truncating mutations were observed in 8.6% of women. In the second study, 3.8% of 130 tumors collected from mastectomy patients in Hong Kong were found to carry protein-truncating mutations in BRCA1 (4). The prevalence was 8.0% in patients diagnosed under age 45 (4). In the same study, investigators observed a single variant, 589delCT, in three unrelated patients from within a single province of Southern China, suggesting a possible founder effect. However a later more detailed study of 60 early onset breast cancer cases did not reveal any additional carriers (4, 5). Neither study examined the role of BRCA2 mutations in Chinese women.Studies of women...

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BRCA1 andBRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age

Cited by 45 publications

References 29 publications

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

BRCA1 and BRCA2 Mutation Prevalence and Clinical Characteristics of a Population-Based Series of Ovarian Cancer Cases from Denmark

BRCA1 and BRCA2 Mutations in Women from Shanghai China

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