Deficiencies in cellular response to DNA damage can predispose to cancer. However, the gene-environment interactions that may be involved in the etiology of these cancers are poorly understood. One important environmental cause of DNA damage is exposure to ionizing radiation leading to the formation of DNA double-strand breaks (DSB). Recent evidence demonstrates that three genes in which mutations predispose to breast cancer, BRCA1/2 and ATM have complex interactions with each other and are essential for the normal cellular response to DSBs. Therefore, interaction between alleles at these loci may have important effects on breast cancer risk, in general, and radiation-induced breast cancer, in particular. To delineate the roles of radiation exposure and genetic predisposition in the etiology of breast cancer, we propose to determine the prevalence of BRCA1/2 mutations in a well characterized population-based sample of 2100 women with breast cancer for whom blood samples have already been obtained and ATM mutation status already determined. Our study hypothesis is that the incidence of contralateral breast cancer will be increased among women who are carriers of mutant BRCA1 or BRCA2 alleles and who received RT as part of treatment for first primary breast cancer. The 700 cases are women with bilateral breast cancer individually countermatched to two controls, women with unilateral breast cancer.
Our specific aims are:
Aim #1. To test for germline BRCA1/2 mutations in a population-based sample of young women with unilateral and bilateral breast cancer, using a staged approach with DHPLC screening followed by sequencing.
Aim #2. To conduct analyses of gene-environment interactions for BRCA1/2 with a focus on radiation exposure. To achieve this aim, we will collect medical/treatment records and recreate the scatter radiation dose to the contralateral breast. Once our study has been completed, we will have established an outstanding resource for future studies of other putative breast cancer genes and environmental exposures, with a particular focus on radiation exposure.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Epidemiology and Disease Control Subcommittee 2 (EDC)
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Seminara, Daniela
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Knight, Julia A; Blackmore, Kristina M; Fan, Jing et al. (2018) The association of mammographic density with risk of contralateral breast cancer and change in density with treatment in the WECARE study. Breast Cancer Res 20:23
Langballe, Rikke; John, Esther M; Malone, Kathleen E et al. (2018) Agreement between self-reported and register-based cardiovascular events among Danish breast cancer survivors. J Cancer Surviv 12:95-100
Reiner, Anne S; Sisti, Julia; John, Esther M et al. (2018) Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women's Environmental Cancer and Radiation Epidemiology Study. J Clin Oncol 36:1513-1520
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Knight, Julia A; Fan, Jing; Malone, Kathleen E et al. (2017) Alcohol consumption and cigarette smoking in combination: A predictor of contralateral breast cancer risk in the WECARE study. Int J Cancer 141:916-924
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Langballe, Rikke; Mellemkjær, Lene; Malone, Kathleen E et al. (2016) Systemic therapy for breast cancer and risk of subsequent contralateral breast cancer in the WECARE Study. Breast Cancer Res 18:65
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Sisti, Julia S; Bernstein, Jonine L; Lynch, Charles F et al. (2015) Reproductive factors, tumor estrogen receptor status and contralateral breast cancer risk: results from the WECARE study. Springerplus 4:825
Rakovski, Cyril; Langholz, Bryan (2015) A post-hoc Unweighted Analysis of Counter-Matched Case-Control Data. Int J Biostat 11:223-32

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