Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer

Women's College Research Institute, University of Toronto, 790 Bay Street, 7th Floor, Toronto, ON, Canada M5G 1N8.
Gynecologic Oncology (Impact Factor: 3.77). 02/2011; 121(2):353-7. DOI: 10.1016/j.ygyno.2011.01.020
Source: PubMed


The heritable fraction of ovarian cancer exceeds that of any other common adult cancer. Most inherited cases of ovarian cancer are due to a germline mutation in BRCA1 or BRCA2. It is important to have an accurate estimate of the proportion of ovarian cancer patients who carry a mutation and the specific factors which predict the presence of a mutation.
We tested a population-based series of 1342 unselected patients diagnosed with invasive ovarian cancer between 1995-1999 and 2002-2004 in Ontario, Canada, for germline mutations in BRCA1 and BRCA2. The two genes were tested in their entirety, using a range of techniques, including multiplex ligation-dependent probe amplification (MLPA).
Among the 1342 women, 176 women carried a mutation (107 in BRCA1, 67 in BRCA2, and two in both genes) for a combined mutation frequency of 13.3%. Seven deletions were identified using MLPA (3.9% of all detected mutations). The prevalence of mutations was particularly high among women diagnosed in their forties (24.0%), in women with serous ovarian cancer (18.0%) and women of Italian (43.5%), Jewish (30.0%) or Indo-Pakistani origin (29.4%). A mutation was seen in 33.9% of women with a first-degree relative with breast or ovarian cancer and in 7.9% of women with no first-degree relative with breast or ovarian cancer. No mutation was seen in women with mucinous carcinoma.
BRCA1 and BRCA2 mutations are common in women with invasive ovarian cancer. All women diagnosed with invasive non-mucinous ovarian cancer should be considered to be candidates for genetic testing.

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    • "Another large population-based study was conducted in Ontario, Canada: among 1342 unselected OC patients, 176 (13%) carried a BRCA1/2 mutation. Higher prevalence of mutations was associated with Italian, Jewish, or Indo- Pakistani origin, serous histology, younger age of onset, and, obviously, a family history of breast or ovarian cancer; among women without family history of such cancers, prevalence was 7.9% [48]. "
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    ABSTRACT: Ovarian cancer (OC) mostly arises sporadically, but a fraction of cases are associated with mutations in BRCA1 and BRCA2 genes. The presence of a BRCA mutation in OC patients has been suggested as a prognostic and predictive factor. In addition, the identification of asymptomatic carriers of such mutations offers an unprecedented opportunity for OC prevention. This review is aimed at exploring the current knowledge on epidemiological and molecular aspects of BRCA-associated OC predisposition, on pathology and clinical behavior of OC occurring in BRCA mutation carriers, and on the available options for managing asymptomatic carriers.
    BioMed Research International 07/2014; 2014:787143. DOI:10.1155/2014/787143 · 3.17 Impact Factor
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    • "We found that 16 % of unselected cases of ovarian cancer in Belarus carried one of three founder mutations in the BRCA1 gene. This is significant higher than in Canada or Poland [11, 12]. A reported family history was a strong predictor of the presence of a mutation, as was a young age of onset. "
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    ABSTRACT: In Belarus and other Slavic countries, founder mutations in the BRCA1 gene are responsible for a significant proportion of breast cancer cases, but the data on contribution of these mutations to ovarian cancers are limited. To estimate the proportion of ovarian cancers in Belarus, which are dependent on BRCA1 Slavic founder mutations, we sought the presence of three most frequent mutations (BRCA1: 5382insC, C61G and, 4153delA) in 158 consecutive unselected cases of ovarian cancer. One of the three founder mutations was present in 25 of 158 unselected cases of ovarian cancer (15.8 %). We recommend that all cases of ovarian cancer in Belarus be offered genetic testing for these founder mutations. Furthermore, genetic testing of the Belarusian population will provide the opportunity to prevent a significant proportion of ovarian cancer.
    Familial Cancer 04/2014; 13(3). DOI:10.1007/s10689-014-9721-8 · 1.98 Impact Factor
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    • "As opposed to the relatively modest impact of hormonal and lifestyle risk factors, a mutation in one of these two genes confers a four- to eightfold increase in the lifetime risk of breast cancer [2, 3]. It also substantially increases the risk for other cancers, in particular the ovarian cancer [4, 5]. Several studies have found evidence for allelic risk heterogeneity, genetic modifiers, and hormonal and lifestyle factors affecting penetrance [6–9]. "
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    ABSTRACT: All women in the South Sweden Health Care Region with breast cancer diagnosed aged less than 41 during the period between 1990 and 1995 were contacted in 1996 and offered germline mutation analysis of the BRCA1 and BRCA2 genes. Mutation carriers (n = 20) were compared with noncarriers (n = 201) for overall survival (OS) and risk of contralateral breast cancer (CBC). Mutation carriers were younger at diagnosis and more likely to have ER-negative, PgR-negative and grade III tumors. Median follow-up was 19 years. The 5-, 10-, 15-, and 20-year OS were 60, 45, 39, and 39 % for mutation carriers and 82, 70, 59, and 53 % for noncarriers, respectively (5-year log-rank P = 0.013; 10-year P = 0.008; 15-year P = 0.020; and 20-year P = 0.046). In univariable analysis, there was a trend for an inferior OS for mutation carriers (HR 1.8; 95 % CI 1.0-3.3). When stratified for use of (neo)adjuvant chemotherapy, an inferior OS was significant only for the subgroup of patients who did not receive chemotherapy (HR 3.0; 95 % CI 1.2-7.7). In multivarible analysis, BRCA1/2 mutation status was a significant predictor of OS when adjusting for tumor stage, age, and use of chemotherapy, but not when ER status was also included in the model. The 15-year cumulative risk of CBC was 53 % for mutation carriers and 10 % for noncarriers (HR 5.9; 95 % CI 1.9-18.6); among the noncarriers the risks were 5, 22, and 30 % for patients without close relatives having breast cancer, with second-degree relatives having breast cancer, and with firstdegree relatives with breast cancer, respectively. In conclusion, the poor prognosis of young BRCA1/2 mutation carriers with breast cancer is mainly explained by the prevalent occurrence of negative prognostic factors rather than mutation status per se, and can to at least some extent be abrogated by the use of chemotherapy.
    Breast Cancer Research and Treatment 01/2014; 144(1). DOI:10.1007/s10549-014-2842-9 · 3.94 Impact Factor
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