A Recurrent ERCC 3 Truncating Mutation Confers Moderate Risk for Breast Cancer

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-defi cient 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-defi cient cells only partially rescued their DNA repair–defi cient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed signifi cant 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 signifi cant 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. Cancer Discov; 6(11); 1267–75. ©2016 AACR. 1 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 2 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. 3 Division of Hematology/ Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 4 Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering, New York, New York. 5 Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. 6 British Columbia Cancer Agency, Canada’s Michael Smith Genome Sciences Centre, Vancouver, Canada. 7 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. 8 Department of Medicine, Weill Cornell Medical College, New York, New York. 9 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California. 10 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York. 11 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. 12 Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B Rappaport Faculty of Medicine, Haifa, Israel. 13 Clinical Cancer Genetics (for the City of Hope Clinical Cancer Genetics Community Research Network), City of Hope, Duarte, California. 14 Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 15 Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 16 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts. 17 Center for Human Genetic Research and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. 18 Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, Minnesota. Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). J. Vijai and S. Topka share fi rst authorship of this article. Corresponding Author: Kenneth Offi t , Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 192, New York, NY 10021. Phone: 646888-4067; Fax: 646-888-4081; E-mail: offi tk@mskcc.org. doi: 10.1158/2159-8290.CD-16-0487 ©2016 American Association for Cancer Research. Research. on October 16, 2017. © 2016 American Association for Cancer cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst September 21, 2016; DOI: 10.1158/2159-8290.CD-16-0487

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