Title
The Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study
Principal Investigator
Jonine Bernstein, PhD
What is the WECARE Study?
The WECARE Study is a large international multi-center, population-based case-control study nested within a cohort of over 52,500 female breast cancer survivors. In this study, 708 women with asynchronous contralateral breast cancer (CBC) serve as cases, and 1397 women with unilateral breast cancer (UBC), individually matched to the cases on age, diagnosis date, latency, and race serve as controls. All participants were recruited through 5 population-based registries in the US and Denmark. Using a multi-faceted approach, this international study examines the interaction of radiation exposure and genetic predisposition in breast cancer, especially radiation-induced contralateral breast cancer (CBC). Currently, we are carrying out studies of: candidate genes BRCA1, BRCA2, CHEK2, and ATM; candidate gene pathways of DNA damage response involved in radiation-induced double strand break repair—ATM, CHEK2, P53 binding protein (53BPI), and MDC1, Mre11, Rad50, and Nbs1 (e.g., MRN nuclease complex); function and mechanism studies of the ATM gene; pharmacogenetics of key drug metabolizing genes; and statistical methods for estimating the cancer risk of rare genetic variants. The global hypothesis across these studies is that women who carry certain types of mutations will be more susceptible to radiogenic breast cancer than non-carriers. The most recent expansion, the WECARE:GWAS Study, was funded to conduct the first multi-stage genome-wide association (GWA) studies of bilateral breast cancer with a built in replication population. We have already completed the genotyping to discover novel common SNPs associated with CBC and radiation exposure. For validation, we are currently in the field recruiting an additional 800 CBC cases and 800 UBC controls from the US, Denmark, and Canada. Various replication and fine-mapping phases are planned as well.
Who Is Conducting this Study?
This study involves a large international group of scientists, with significant experience in specialties such as molecular genetics, radiation epidemiology/dosimetry and quantitative epidemiologic methods. Collaborating sites include:
- Memorial Sloan Kettering Cancer Center: Jonine Bernstein PhD, Colin Begg PhD, Marinela Capanu PhD, Irene Orlow PhD, Robert Klein PhD, Ken Offit MD, Xiaolin Liang, MD, Anne Reiner MPH, Meghan Woods
- City of Hope: Leslie Bernstein PhD (sub PI), Laura Donnelly-Allen
- Danish Cancer Society: Jørgen Olsen MD DMSc (Sub PI), Michael Andersson MD, Lisbeth Bertelsen MSc, Per Guldbergj PhD, Lene Mellemkjær PhD
- Fred Hutchinson Cancer Research Center: Kathleen Malone PhD (Sub PI), Noemi Epstein
- International Epidemiology Institute/Vanderbilt University: John D. Boice Jr. ScD (Sub PI)
- Lund University: Åke Borg PhD (Sub PI),Theresa Sandberg PhD
- Mount Sinai School of Medicine: Barry Rosenstein PhD (Sub PI), David Atencio PhD
- National Cancer Institute: Daniela Seminara PhD MPH
- New York University: Roy Shore PhD, DrPH.(Sub PI)
- Northern California Cancer Center: Esther John PhD (Sub PI), Ellen Chang ScD
- Norwegian Radium Hospital: Anne-Lise Børresen-Dale PhD (Sub PI), Laila Jansen
- Samuel Lunenfeld Research Institute: Julia Knight PhD (Sub PI), Anna Chiarelli PhD
- Stanford University: Alice Whittemore PhD
- Translational Genomics Research Institute (T-Gen): David Duggan PhD (Sub PI)
- University of California Irvine: Hoda Anton-Culver PhD (Sub PI), Joan Largent PhD MPH
- University of California Los Angeles: Richard Gatti MD
- University of Iowa: Charles Lynch MD, PhD (Sub PI), Jeanne DeWall MA
- University of Southern California: Robert Haile DrPH (Sub PI), Graham Casey PhD, Bryan Langholz PhD, Daniel Stram PhD, Duncan Thomas PhD, Anh Diep, Shanyan Xue MD, Nianmin Zhou,MD, Yong Liu MD, Evgenia Ter-Karapetova, Andre Hernandez;
- University of Southern Maine: W. Douglas Thompson PhD (Sub PI)
- University of Texas, MD Anderson Cancer Center: Marilyn Stovall PhD (Sub PI), Susan Smith MPH, Thomas Buchhlz MD
- University of Virginia: Patrick Concannon PhD (Sub PI), Sharon Teraoka PhD, Eric Olson PhD
Study Objective
To examine the interaction of radiation exposure and genetic susceptibility in the etiology of second primary breast cancer
Study Hypothesis
The global hypothesis across all of the WECARE Studies is that women who are carriers of certain genetic mutations will be more susceptible to radiation-induced breast cancer than are non-carriers.
Project Members
Bernstein JL, Seminara D, Børresen-Dale, A-L. Workshop on The Epidemiology of the ATM Gene: Impact on Breast Cancer Risk and Treatment, Present Status and Future Focus, Lillehammer, Norway, 29 June 2002. Breast Cancer Res 2002; 4:249-252.
Bernstein JL, Teraoka S, Haile RW, et al. Designing and implementing quality control for multi-center screening of mutations in the ATM gene among women with breast cancer. Hum Mutat 2003; 21:542-500.
Bernstein JL, Bernstein L, Thompson WD, et al. ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer. Br J Cancer 2003; 89:1513-1516.
Bernstein JL, Langholz BM, Haile RW, et al. Research Design: Evaluating gene-environment interactions in the etiology of breast cancer - the WECARE Study. Breast Cancer Res 2004; 6:R199-R214
Bernstein JL, Concannon P, Langholz B, et al. Multi-center screening of mutations in the ATM gene among women with breast cancer - the WECARE Study. Radiat Res 2005; 163:698-699.
Langholz B, Bernstein JL, Bernstein L, et al. On the proposed association of the ATM variants 5557G>A and IVS38-8T>C and bilateral breast cancer. Int J Cancer 2006; 119:724-725.
Langholz B, Thomas DC, Stovall M, et al. Analysis of radiation dose-response with tumor location and location-specific dose in the WECARE Study of second breast cancer. Radiation Research 2007; 167:358-359.
Largent JA, Capanu M, Bernstein L, et al. Reproductive history and risk of second primary breast cancer: the WECARE Study. Cancer Epidemiol Biomarkers Prev. 2007; 5:906-911.
Bertelsen L, Bernstein L, Olsen JH, et al. Effect of systemic adjuvant treatment on risk for contralateral breast cancer in the Women's Environment, Cancer and Radiation Epidemiology Study. J Natl Cancer Inst. 2008; 100(1):32-40.
Begg CB, Haile RW, Borg A, et al. Variation of breast cancer risk among BRCA1/2 carriers. JAMA 2008; 299(2):194-201.
Figueiredo JC, Bernstein L, Capanu M, et al. Oral contraceptives, post-menopausal hormones and risk of asynchronous bilateral breast cancer: The WECARE Study Group. J Clin Oncol. 2008; 26(9):1411-8.
Mellemkjær L, Dahl C, Olsen JH, et al. Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study. Br J Cancer. 2008; 98(4):728-733.
Stovall M, Smith SA, Langholz BM, et al. Dose to the contralateral breast from radiation therapy and risk of second primary breast cancer in the WECARE study. Int J Radiat Oncol Biol Phys. 2008; 72:1021-1030.
Langholz B, Thomas DC, Stovall M, et al. Statistical methods for analysis of radiation effects with tumor and dose location-specific information with application to the WECARE Study of asynchronous contralateral breast cancer. Biometrics 2009;65(2):599-608.
Concannon P, Haile RW, Børresen-Dale A, et al. Variants in the ATM gene associated with a reduced risk of contralateral breast cancer. Cancer Research 2008; 15;68(16):6486-6491.
Knight J, Bernstein L, Largent J, et al. Alcohol intake and cigarette smoking and risk of a contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study. American Journal of Epidemiology February 11, 2009 [Epub ahead of print]
Figueiredo JC, Haile RW, Bernstein JL. Oral Contraceptives and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. Current Breast Cancer Reports. June 2009
Figueiredo JC, Haile RW, Bernstein L, et al. Oral contraceptives and postmenopausal hormones and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers and noncarriers: the WECARE Study. Breast Cancer Res Treat. 2009 Jul 14. [Epub ahead of print]
Bernstein JL, Haile RW, Stovall M, et al. Radiation exposure, the ATM gene, and contralateral breast cancer in the WECARE Study. J Natl Cancer Inst. August 2009. [Accepted]
