Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer-affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair-deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (OR BC = 1.53, OR ER+ = 1.73), particularly for the estrogen receptor-positive subset (P < 0.007). SIGNIFICANCE: A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers.
Bibliographical noteFunding Information:
This work was supported by the Sharon Corzine Cancer Research Fund, The Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Miele family initiative (K. Offit), and the Andrew Sabin Family Fund. This work was also supported by NIH R01CA176785 and the Breast Cancer Research Foundation (F.J. Couch, K.L. Nathanson, M. Robson, and K. Offit), R21-CA139396 (J. Vijai and Z.K. Stadler), and Department of Defense W81XWH-13-1-0338 (K.L. Nathanson). This work was also supported by funds from the City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, NIH. This work was also supported by the MSKCC Core grant NIH P30CA008748.
© 2016 American Association for Cancer Research.