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

Abstract

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.

Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel

“…BRCA1 genotyping BRCA1 genotyping was performed by exon-specific amplification using flanking intronic primers and primers designed to generate slightly overlapping fragments from exon 11, as previously described [30]. No analysis for large genomic rearrangements of BRCA1 was performed.…”

“…BRCA2 genotyping BRCA2 genotyping was performed by exon-specific amplification using flanking intronic primers and primers designed to generate slightly overlapping fragments from exon 11, as previously described [30]. In a subset of participants (some of the non Ashkenazim, the Moslem and Druze participants) BRCA2 mutational analysis was performed using heteroduplex analysis (HDA) using enhanced mismatch mutation analysis (EMMA) technique supplemented by sequencing of abnormally migrating fragments, as previously described [31].…”

Identification of a novel BRCA1 nucleotide 4803delCC/c.4684delCC mutation and a nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in two Greenlandic Inuit families: implications for genetic screening of Greenlandic Inuit families with high risk for breast and/or ovarian cancer

“…Moreover, several founder mutations have been reported in BRCA1 and BRCA2, including the Icelandic BRCA2 nucleotide 999del5, and the Ashkenazi Jews BRCA1 nucleotide 185delAG mutations, which are found with frequencies between 0.6 and 1.0% in the population [7][8][9][10]. In Denmark, multiple disease-causing BRCA1/BRCA2 mutations have been identified [11][12][13][14][15]. However, only one disease-causing mutation (p.Cys39Gly) has been identified in Greenlandic Inuits [16].…”

Identification of Germline BRCA1 Mutations among Breast Cancer Families in Northeastern Iran

“…In Sweden, six mutations, including 3172ins5 and 1201del11 in BRCA1, accounted for 75% of mutations in a clinical screening unit (Einbeigi et al, 2007). Finally, in Denmark, the 2594delC mutation has been shown to account for 18% of all BRCA1 mutations (Sogaard et al, 2008) and 7 mutations account for 35% of carriers. Most family physicians believed that identifying familial cancer risk in their patients was important, but did not feel confident doing so (Freedman et al, 2003).…”