Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes
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Rory L. Cochran1, Justin Cidado3, Minsoo Kim1, Daniel J. Zabransky1, Sarah Croessmann1, David Chu1, Hong Yuen Wong1, Julia A. Beaver1, Karen Cravero1, Bracha Erlanger1, Heather Parsons1, Christopher M. Heaphy1, Alan K. Meeker1, Josh Lauring1 and Ben Ho Park1,2
1 The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 The Whiting School of Engineering, Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA
3 Oncology iMED, AstraZeneca, Waltham, MA, USA
Ben Ho Park, email:
Keywords: BRCA1, VUS, breast cancer, haploinsufficiency, centrosome amplification
Received: June 01, 2015 Accepted: June 01, 2015 Published: June 23, 2015
Clinical genetic testing of BRCA1 and BRCA2 is commonly performed to identify specific individuals at risk for breast and ovarian cancers who may benefit from prophylactic therapeutic interventions. Unfortunately, it is evident that deleterious BRCA1 alleles demonstrate variable penetrance and that many BRCA1 variants of unknown significance (VUS) exist. In order to further refine hereditary risks that may be associated with specific BRCA1 alleles, we performed gene targeting to establish an isogenic panel of immortalized human breast epithelial cells harboring eight clinically relevant BRCA1 alleles. Interestingly, BRCA1 mutations and VUS had distinct, quantifiable phenotypes relative to isogenic parental BRCA1 wild type cells and controls. Heterozygous cells with known deleterious BRCA1 mutations (185delAG, C61G and R71G) demonstrated consistent phenotypes in radiation sensitivity and genomic instability assays, but showed variability in other assays. Heterozygous BRCA1 VUS cells also demonstrated assay variability, with some VUS demonstrating phenotypes more consistent with deleterious alleles. Taken together, our data suggest that BRCA1 deleterious mutations and VUS can differ in their range of tested phenotypes, suggesting they might impart varying degrees of risk. These results demonstrate that functional isogenic modeling of BRCA1 alleles could aid in classifying BRCA1 mutations and VUS, and determining BRCA allele cancer risk.
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