A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer Journal Article


Authors: Vijai, J.; Topka, S.; Villano, D.; Ravichandran, V.; Maxwell, K. N.; Maria, A.; Thomas, T.; Gaddam, P.; Lincoln, A.; Kazzaz, S.; Wenz, B.; Carmi, S.; Schrader, K. A.; Hart, S. N.; Lipkin, S. M.; Neuhausen, S. L.; Walsh, M. F.; Zhang, L.; Lejbkowicz, F.; Rennert, H.; Stadler, Z. K.; Robson, M.; Weitzel, J. N.; Domchek, S.; Daly, M. J.; Couch, F. J.; Nathanson, K. L.; Norton, L.; Rennert, G.; Offit, K.
Article Title: A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer
Abstract: 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. © 2016 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 6
Issue: 11
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2016-11-01
Start Page: 1267
End Page: 1275
Language: English
DOI: 10.1158/2159-8290.cd-16-0487
PROVIDER: scopus
PUBMED: 27655433
PMCID: PMC5614601
DOI/URL:
Notes: Article -- Export Date: 6 December 2016 -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    494 Offit
  2. Larry Norton
    541 Norton
  3. Mark E Robson
    358 Robson
  4. Liying Zhang
    86 Zhang
  5. Zsofia Kinga Stadler
    139 Stadler
  6. Vijai Joseph
    113 Joseph
  7. Tinu Mary Thomas
    15 Thomas
  8. Danylo Julian Villano
    13 Villano
  9. Ann   Maria
    7 Maria
  10. Anne Gunning Lincoln
    14 Lincoln
  11. Sabine   Topka
    6 Topka
  12. Pragna   Gaddam
    9 Gaddam
  13. Michael Francis Walsh
    43 Walsh
  14. Sarah Allison Kazzaz
    1 Kazzaz