Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer
ABSTRACT 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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ABSTRACT: Breast cancer and gynecological cancers impact a significant portion of women each year. Identifying women at high risk is essential for implementation of screening and risk reduction recommendations. Risk assessment for these cancers involves an evaluation of many factors. This review discusses an overview of hereditary breast and gynecological cancers and the process of a cancer genetic risk assessment. Risk assessment models for breast cancer should be used with caution, especially in populations in which they are not validated. Additionally, the BRCAPRO model may underestimate the likelihood of BRCA mutations in certain populations.The utilization of next-generation sequencing panels is increasing. Benefits and limitations of panel testing are described in the literature. There are currently no guidelines for the use of panel testing; however, some reports of institutional experiences and recommendations are available. Cancer genetic risk assessment is complex, and models developed to estimate risk may not apply to all populations. Identifying genetic factors related to cancer risk is also becoming increasingly complex with the clinical implementation of panel testing. This testing approach should be critically evaluated by healthcare providers. Further research is needed to create evidence-based guidelines for panel testing and management recommendations for moderately penetrant genes.Current Opinion in Obstetrics and Gynecology 12/2014; 27(1). DOI:10.1097/GCO.0000000000000142 · 2.37 Impact Factor
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ABSTRACT: Purpose:To analyse the effect of germline mutations in BRCA1 and BRCA2 on mortality in ovarian cancer patients up to ten years after diagnosis. Experimental Design:We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival-time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analysed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analysed using Fine and Gray model. Results: The combined 10-year overall survival was 30% (95% CI, 28%-31%) for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The hazard ratio for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the hazard ratio was 0.42 at time zero and increased over time (predicted to become greater than one at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors, and to ovarian cancer specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and, in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
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ABSTRACT: Technological advances in DNA sequencing have made gene testing fast and affordable, but there are challenges to the translation of these improvements for patient benefit. The Mainstreaming Cancer Genetics (MCG) programme is exploiting advances in DNA sequencing to develop the infrastructure, processes and capabilities required for cancer gene testing to become routinely available to all those that can benefit. The MCG programme held a consultation day to discuss the development of cancer genetics with senior representation from all 24 UK cancer genetic centres. The current service landscape and capacity for expansion was assessed through structured questionnaires. Workshop discussion addressed the opportunities and challenges to increasing cancer gene testing in the National Health Service (NHS). Services vary with respect to population served and models of service delivery, and with respect to methods and thresholds for determining risk and testing eligibility. Almost all centres want to offer more cancer gene testing (82%) and reported increasing demand for testing from non-genetic clinical colleagues (92%). Reported challenges to increasing testing include the complexity of interpreting the resulting genetic data (79%), the level of funding and complexity of commissioning (67%), the limited capacity of current processes and cross-disciplinary relationships (38%), and workforce education (29%). Priorities to address include the development and evaluation of models of increasing access to gene testing, the optimal process for interpretation of large-scale genetic data, implementation of appropriate commissioning and funding processes, and achieving national consistency. The UK cancer genetics community have high expertise and strong commitment to maximising scientific advances for improved patient benefit and should be pivotally involved in the implementation of increased cancer gene testing.Genome Medicine 01/2015; 7(1):18. DOI:10.1186/s13073-015-0128-4 · 4.94 Impact Factor