Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes

Rory L. Cochran, Justin Cidado, Minsoo Kim, Daniel J. Zabransky, Sarah Croessmann, David Chu, Hong Yuen Wong, Julia A. Beaver, Karen Cravero, Bracha Erlanger, Heather Parsons, Christopher M. Heaphy, Alan K. Meeker, Josh Lauring, Ben Ho Park

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)25240-25251
Number of pages12
JournalOncotarget
Volume6
Issue number28
DOIs
StatePublished - Jan 1 2015

Keywords

  • BRCA1
  • Breast cancer
  • Centrosome amplification
  • Haploinsufficiency
  • VUS

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Cochran, R. L., Cidado, J., Kim, M., Zabransky, D. J., Croessmann, S., Chu, D., Wong, H. Y., Beaver, J. A., Cravero, K., Erlanger, B., Parsons, H., Heaphy, C. M., Meeker, A. K., Lauring, J., & Park, B. H. (2015). Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes. Oncotarget, 6(28), 25240-25251. https://doi.org/10.18632/oncotarget.4595