Mahrukh M Syeda1, Kinnari Upadhyay1, Johnny Loke1, Alexander Pearlman1, Susan Klugman2, Yongzhao Shao3, Harry Ostrer1. 1. Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA. 2. Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, New York, USA. 3. Department of Population Health, Division of Biostatistics, New York University School of Medicine, New York, New York, USA.
Abstract
PURPOSE: Identifying women at high risk for breast cancer can trigger a personal program of annual mammograms and magnetic resonance imaging scans for early detection, prophylactic surgery, or chemoprevention to reduce the risk of cancer. Yet, current strategies to identify high-risk mutations based on sequencing panels of genes have significant false-positive and false-negative results, suggesting the need for alternative approaches. METHODS: Flow-variant assays (FVAs) that assess the effects of mutations in the double-strand break (DSB) repair genetic pathway in lymphoblastoid cells in response to treatment with radiomimetic agents were assessed for sensitivity, specificity, and accuracy both alone and as part of a logistic regression classification score. In turn, these assays were validated in circulating B cells and applied to individuals with personal and/or family history of breast and/or ovarian cancer. RESULTS: A three-FVA classification score based on logistic regression had 95% accuracy. Individuals from a breast cancer-positive cohort with affected family members had high-risk FVA classification scores. CONCLUSION: Application of a classification score based on multiple FVAs could represent an alternative to panel sequencing for identifying women at high risk for cancer.Genet Med advance online publication 16 March 2017.
PURPOSE: Identifying women at high risk for breast cancer can trigger a personal program of annual mammograms and magnetic resonance imaging scans for early detection, prophylactic surgery, or chemoprevention to reduce the risk of cancer. Yet, current strategies to identify high-risk mutations based on sequencing panels of genes have significant false-positive and false-negative results, suggesting the need for alternative approaches. METHODS: Flow-variant assays (FVAs) that assess the effects of mutations in the double-strand break (DSB) repair genetic pathway in lymphoblastoid cells in response to treatment with radiomimetic agents were assessed for sensitivity, specificity, and accuracy both alone and as part of a logistic regression classification score. In turn, these assays were validated in circulating B cells and applied to individuals with personal and/or family history of breast and/or ovarian cancer. RESULTS: A three-FVA classification score based on logistic regression had 95% accuracy. Individuals from a breast cancer-positive cohort with affected family members had high-risk FVA classification scores. CONCLUSION: Application of a classification score based on multiple FVAs could represent an alternative to panel sequencing for identifying women at high risk for cancer.Genet Med advance online publication 16 March 2017.
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