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Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes.

ABSTRACT: 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.

SUBMITTER: Cochran RL

PROVIDER: S-EPMC4694828 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes.

Cochran Rory L RL Cidado Justin J Kim Minsoo M Zabransky Daniel J DJ Croessmann Sarah S Chu David D Wong Hong Yuen HY Beaver Julia A JA Cravero Karen K Erlanger Bracha B Parsons Heather H Heaphy Christopher M CM Meeker Alan K AK Lauring Josh J Park Ben Ho BH

Oncotarget 20150901 28

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 iso ...[more]

PMID: 26246475

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Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes.

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Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes.

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