Women's Environmental Cancer and Radiation Epidemiology Study (WECARE)

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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, 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.

References

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, Borreson-Dale AL, Rosenstein BS, Diep A, Atencio D, Teitelbaum S, Thompson WD, Bernstein L, Anton-Culver H, Malone K, Lynch CF, Boice Jr. JD, Gatti RA, Langholz BM, Olsen JH, Stovall M, Thomas D, Concannon PJ. 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, Langholz BM, Haile RW, Bernstein L, Thomas DC, Stovall M, Malone KE, Lynch CF, Olsen JH, Anton-Culver H, Shore RE, Boice Jr. JD, Berkowitz GS, Gatti RA, Teitelbaum SL, Smith SA, Rosenstein BS, Borresen-Dale, AL, Concannon P, Thompson WD. 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, Thompson WD, Bernstein L, Stovall M, Thomas DC;WECARE Study Collaborative Group. Multi-center screening of mutations in the ATM gene among women with breast cancer—the WECARE Study. Radiat Res 2005; 163:698-699.

Read more

Langholz B, Bernstein JL, Bernstein L, Olsen JH, Borresen-Dale AL, Rosenstein BS, Gatti RA, Concannon P. 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, Smith S, Boice JD, Shore RE, Bernstein JL. 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, Langholz B, Mellemkjaer L, Malone KE, Begg CB, Haile RW, Lynch CF, Anton-Culver H, Wolitzer A, Bernstein JL. 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, Mellemkjaer L, Haile RW, Lynch CF, Malone KE, Anton-Culver H, Christensen J, Langholz B, Thomas DC, Begg CB, Capanu M, Ejlertsen B, Stovall M, Boice JD Jr, Shore RE, Women’s Environment, Cancer and Radiation Epidemiology Study Collaborative Group, Bernstein JL. 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, BorgA, Malone KE, Concannon P, Thomas DC,Langholz B, Bernstein L, Olsen JH, Lynch CF, Anton-Culver H, Capanu H, Liang X, Hummer AJ, Sima C, Bernstein JL. Variation of breast cancer risk among BRCA1/2 carriers. JAMA 2008; 299(2):194-201.

Figueiredo JC, Bernstein L, Capanu M, Malone KE, Lynch CF, Anton-Culver H,  Stovall M, Børresen-Dale A, Haile RW, Bernstein JL, The WECARE Study Collaborative Group. Oral contraceptives, post-menopausal hormones and risk of asynchronous bilateral breast cancer: The WECARE Study Group. J Clin Oncol 2008; 26(9):1411-1418.

Mellemkjær L, Dahl C, Olsen JH, Bertelsen L, Guldberg P, Christensen J, Børresen-Dale A-L, Stovall M, Langholz B, Bernstein L, Lynch CF, Malone KE, Haile RW, Andersson M, Thomas DC, Concannon P, Capanu M, Boice JD,  The WECARE Study Collaborative Group12, Bernstein JL. 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, Boice JD, Shore RE, Andersson M, Buchholz TA, Capanu M, Bernstein L, Lynch CF, Malone KE, Anton-Culver H, Haile RW, Reiner A, Thomas DC, Bernstein JL. 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.

Concannon P, Haile RW, Børresen-Dale AL, Rosenstein BS, Gatti RA, Teraoka SN, Diep TA, Jansen L, Atencio DP, Langholz B, Capanu M, Liang X, Begg CB, Thomas DC, Bernstein L, Olsen JH, Malone KE, Lynch CF, Anton-Culver H, Bernstein JL; Women’s Environment, Cancer, and Radiation Epidemiology Study Collaborative Group. Variants in the ATM gene associated with a reduced risk of contralateral breast cancer. Cancer Res 2008; 68(16):6486-6491.

Langholz B, Thomas DC, Stovall M, Smith SA, Boice JD, Jr., Shore RE, Bernstein L, Lynch CF, Zhang X, Bernstein JL. 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.

Knight JA, Bernstein L, Largent J, Capanu M, Begg CB, Mellemkjaer L, Lynch CF, Malone KE, Reiner AS, Liang X, Haile RW, Boice JD Jr; WECARE Study Collaborative Group, Bernstein JL. Alcohol intake and cigarette smoking and risk of a contralateral breast cancer: The Women’s Environmental Cancer and Radiation Epidemiology Study. Am J Epidemiol 2009; 169(8):962-968.

Figueiredo JC, Haile RW, Bernstein JL. Oral contraceptives and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Current Breast Cancer Reports 2009; 1(3):139-147.

Figueiredo JC, Haile RW, Bernstein L, Malone KE, Largent J, Langholz B, Lynch CF, Bertelsen L, Capanu M, Concannon P, Borg A, Børresen-Dale AL, Diep A, Teraoka S, Torngren T, Xue S, Bernstein JL. 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 2010; 120(1):175-183.

Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale AL, Bernstein JL. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat 2010; 31(3):E1200-1240.

Poynter JN, Langholz B, Largent J, Mellemkjaer L, Bernstein L, Malone KE, Lynch CF, Borg A, Concannon P, Teraoka SN, Xue S, Diep AT, Törngren T, Begg CB, Capanu M, Haile RW; WECARE Study Collaborative Group, Bernstein JL. Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study. Cancer Causes Control 2010; 21(6):839-846.

Reding KW, Bernstein JL, Langholz BM, Bernstein L, Haile RW, Begg CB, Lynch CF, Concannon P, Borg A, Teraoka SN, Törngren T, Diep A, Xue S, Bertelsen L, Liang X, Reiner AS, Capanu M, Malone KE; WECARE Collaborative Study Group. Adjuvant systemic therapy for breast cancer in BRCA1/BRCA2 mutation carriers in a population-based study of risk of contralateral breast cancer. Breast Cancer Res Treat 2010; 123(2):491-498.

Bernstein JL, Haile RW, Stovall M, Boice JD Jr, Shore RE, Langholz B, Thomas DC, Bernstein L, Lynch CF, Olsen JH, Malone KE, Mellemkjaer L, Borresen-Dale AL, Rosenstein BS, Teraoka SN, Diep AT, Smith SA, Capanu M, Reiner AS, Liang X, Gatti RA, Concannon P; The WECARE Study Collaborative Group. Radiation exposure, the ATM Gene, and contralateral breast cancer in the women’s environmental cancer and radiation epidemiology study. J Natl Cancer Inst 2010; 102(7):475-483.

Malone KE, Begg CB, Haile RW, Borg A, Concannon P, Tellhed L, Xue S, Teraoka S, Bernstein L, Capanu M, Reiner AS, Riedel ER, Thomas DC, Mellemkjaer L, Lynch CF, Boice JD Jr, Anton-Culver H, Bernstein JL. Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol 2010; 28(14):2404-2410.

Figueiredo JC, Brooks JD, Conti DV, Poynter JN, Teraoka SN, Malone KE, Bernstein L, Lee WD,  Duggan DJ, Siniard A, Concannon P, Capanu  M, Lynch CF, Olsen JH, Haile RW and Bernstein JL. Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: Potential modifying effect of BRCA1/BRCA2 mutation carrier status. Breast Cancer Res Treat 2011; 127(3):819-29.

Capanu M, Concannon P, Haile RW, Bernstein L, Malone KE, Lynch CF, Liang X, Teraoka SN, Diep AT, Thomas DC, Bernstein JL, The WECARE Study Collaborative Group, Begg CB. Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling. Genet Epidemiol 2011; 35(5):389-397.

King V, Brooks JD, Bernstein JL, Reiner AS, Pike MC, Morris EA. Background Parenchymal Enhancement on Breast MRI and Breast Cancer Risk. Radiology 2011; 260(1):50-60.

Brooks JD, Teraoka SN, Reiner AS, Satagopan JM, Bernstein L, Thomas DC, Capanu M, Stovall M, Smith SA, Wei S, Shore RE, Boice, Jr. JD, Lynch CF, Mellemkjær L, Malone KE, Liang X, the WECARE Study Collaborative Group, Haile RW, Concannon P and Bernstein JL. Variants in activators and downstream targets of ATM, radiation exposure and contralateral breast cancer risk in the WECARE Study. Hum Mutat 2012; 33(1):158-64.

Brooks JD, John EM, Mellemkjaer L, Reiner AS, Malone KE, Lynch CF, Figueiredo JC, Haile RW, Shore RE; The WECARE Study Collaborative Group, Bernstein JL, Bernstein L. Body mass index and risk of second primary breast cancer: The WECARE Study. Breast Cancer Res Treat 2012; 131(2):571-580.

Tischkowitz M, Capanu M, Sabbaghian N, Li L, Liang X, Vallee M, Tavtigian S, Concannon P, Foulkes WD, Bernstein L, Bernstein JL, Begg CB. Rare Germline Mutations in PALB2 and Breast Cancer Risk: A Population-Based Study.  Hum Mutat 2012; 33(4):674-80.

Brooks JD, Boice JD, Jr, Stovall M, Reiner AS, Bernstein L, John EM, Lynch CF, Mellemkjær L, Knight JA, Thomas DC, Haile RW, Smith SA, Capanu C, The WECARE Collaborative Group, Bernstein JL, Shore RE. Reproductive status at first diagnosis influences risk of radiation-induced second primary contralateral breast cancer in The WECARE Study. Int J Radiat Oncol Biol Phys 2012.

Teraoka SN, Bernstein JL, Reiner AS, Haile RW, Bernstein L, Lynch CF, Malone KE, Stovall M, Capanu M, Liang X, Smith SA, Mychaleckyj J, Hou X, Mellemkjaer L, Boice Jr. JD, Siniard A, Duggan D, Thomas DC, The WECARE Study Collaborative Group, and Concannon P. Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women’s Environment, Cancer and Radiation Epidemiology (WECARE) study. Breast Cancer Res; 13(6):R114.

Brooks JD,  Bernstein L, Teraoka S, Knight JA, Mellemkjær L,  John EM, Malone KE, Reiner AS, Lynch C, Concannon P, Haile RW, Bernstein JL.Variation in genes related to obesity, weight and weight change and risk of contralateral breast cancer in the WECARE Study population. Cancer Epidemiol Biomark Prev 2012; 21(12): 2261-7.

Reiner AS, John E, Brooks JD, Lynch CF, Bernstein L, Mellemkjær L, Malone KE, Knight JA, Capanu M, Teraoka SN, Concannon P, Liang X, Figueiredo JC, Smith SA, Stovall M, Pike MC,  Haile RW, Thomas DC, Begg CB, The WECARE Study Collaborative Group, Bernstein JL. Risk of asynchronous contralateral breast cancer in non-carriers of BRCA1 and BRCA2 mutations with a family history of breast cancer: A report from the WECARE Study. J Clin Oncol 2013; 31(4):433-9.

Quintana MA, Schumacher F,Casey G, Bernstein JL, Li L, and Conti DV. Incorporating prior biologic information for high dimensional rare variant association studies. Hum Hered 2012; 74(3-4):184-95.

Brooks JD, Teraoka S, Malone K, Haile R, Bernstein L, Lynch CF, Mellemkjaer L, Duggan D, Reiner AS, Lewinger J, Figueiredo J, Bernstein JL. Variants in tamoxifen metabolizing genes: A case-control study of contralateral breast cancer risk in the WECARE Study. Int J Mol Epidemiol Genet 2013; 4(1):35-48.

Bernstein JL,  Thomas DC, Shore R, Robson ME, Boice J, Stovall M, Andersson M, Bernstein L, Malone K, Reiner AS, Lynch C, Capanu M, Smith SA, Tellhed L, Teraoka SN, Begg CB, Olsen J, Mellemkjaer L, Liang X, Diep A, Borg A, Concannon P, Haile RW, The WECARE Study Collaborative Group. Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers: A WECARE Study report. Eur J Cancer 2013 pii: S0959-8049(13)00362-6.

Brooks JD, Teraoka SN, Bernstein L, Mellemkjær L, Malone KE, Lynch CF, Haile RW, Concannon P, Reiner AS, Duggan DJ, Schiermeyer K, The WECARE Study Collaborative Group, Bernstein JL , Figueiredo JC. Common variants in genes coding for chemotherapy metabolizing enzymes, transporters and targets:  A case-control study of contralateral breast cancer risk in the WECARE Study. Cancer Causes Control  2013; 24(8):1605-14.

Moskowitz CS, Chou JF, Wolden SL, Bernstein JL, Malhotra J, Friedman DN, Mubdi NZ, Henderson TO, Leisenring WM, Stovall M, Hammond S, Smith SA, Boice JD, Hudson MM, Diller LR, Bhatia S, Kenney L, Neglia JP, Begg CB, Robison LL, Oeffinger KC. Breast cancer after chest radiation therapy for a childhood cancer. Lancet 2013.

Duan L, Thomas DC, The WECARE Study Collaborative Group. A Bayesian hierarchical model for relating multiple SNPs within multiple genes to disease risk. Int J Genom 2013. [In Press]

Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkas K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F, Tomiak E, Neuhausen S, Teo ZL, Khan S, Aittomaki K, Moilanen JS, Turnbull C, Seal S, Mannermaa A, Kallioniemi A, Buys SS, Andrulis I, Radice P, Tondini C, Manoukian S, Toland A, Miron P, kConFab, Weitzel JN, Domchek S, Poppe B, Claes KBM, Yannoukakos D, Concannon P, Bernstein J, James P, Easton D, Goldgar DE, Hopper JL, Rahman N, Peterlongo P, Nevanlinna H, King M, Couch FJ, Southey MC, Winqvist R, Foulkes WD, Tischkowitz M. PALB2 is a high-risk breast cancer susceptibility gene: a kin-cohort analysis of 154 families. NEJM 2013.

 

Project Members

Jonine Lisa Bernstein
Anne S. Reiner

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