Variants in activators and downstream targets of ATM, radiation exposure, and contralateral breast cancer risk in the WECARE study

Jennifer D. Brooks, Sharon N. Teraoka, Anne S. Reiner, Jaya M. Satagopan, Leslie Bernstein, Duncan C. Thomas, Marinela Capanu, Marilyn Stovall, Susan A. Smith, Shan Wei, Roy E. Shore, John D. Boice, Charles F. Lynch, Lene Mellemkjær, Kathleen E. Malone, Xiaolin Liang, Robert W. Haile, Patrick Concannon, Jonine L. Bernstein, Colin BeggIrene Orlow, Robert Klein, Ken Offit, Meghan Woods, Esther M. John, Wei Wang, Jørgen H. Olsen, Noemi Epstein, Daniela Seminara, Julia Knight, Anna Chiarelli, David Duggan, Jeanne DeWall, Daniel Stram, Anh T. Diep, Shanyan Xue, Nianmin Zhou, Evgenia Ter-Karapetova, Susan Smith, Sharon Teraoka, Eric R. Olson, V. Anne Morrison, Lemuel Navarro, Karen M. Cerosaletti, Jocyndra Wright

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Ionizing radiation (IR) is a breast carcinogen that induces DNA double-strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation-induced breast cancer. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) study is a populationbased study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received by the contralateral breast was estimated from radiotherapy records and mathematical models. One hundred fifty-two SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases and 1,284 controls) and no variants were found to interact with radiation dose. Carriers of a RAD50 haplotype exposed to ≥1 gray (Gy) had an increased risk of CBC compared with unexposed carriers (Rate ratios [RR] = 4.31 [95% confidence intervals [CI] 1.93-9.62]); with an excess relative risk (ERR) per Gy = 2.13 [95% CI 0.61-5.33]). Although the results of this study were largely null, carriers of a haplotype in RAD50 treated with radiation had a greater CBC risk than unexposed carriers. This suggests that carriers of this haplotype may be susceptible to the DNA-damaging effects of radiation therapy associated with radiationinduced breast cancer.

Original languageEnglish (US)
Pages (from-to)158-164
Number of pages7
JournalHuman mutation
Volume33
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Keywords

  • Contralateral breast cancer
  • DNA repair
  • Haplotypes
  • Polymorphisms
  • Radiation

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