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Grant Details

Grant Number: 5R01CA129639-05 Interpret this number
Primary Investigator: Bernstein, Jonine
Organization: Sloan-Kettering Inst Can Research
Project Title: Genome-Wide Association Study of Radiation Exposure and Bilateral Breast Cancer
Fiscal Year: 2013
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Abstract

DESCRIPTION (provided by applicant): To delineate the joint roles of genetic predisposition and radiation exposure in the etiology of second primary breast cancer, we propose to apply a genome-wide association (GWA) approach to women with bilateral breast cancer for whom we have detailed radiation dose estimates. The existing study population consists of 708 women with asynchronous bilateral breast cancer (cases) and 1,399 women with unilateral breast cancer (matched controls). In addition, through four cancer registries in the US and one in Denmark, we will recruit, interview and obtain a blood sample from 800 women with bilateral breast cancer (new cases) and 800 women with unilateral breast cancer (new controls). Our Specific Aims are as follows: AIM 1: Identify SNPs that are associated with bilateral breast cancer using a two-stage approach in a population-based case-control study. In Stage 1 for Discovery, perform a GWA study of bilateral and unilateral breast cancers to identify common SNPs associated with the incidence of bilateral breast cancer using the existing cases and controls. In Stage 2 for Validation, evaluate the 6,000 most significant SNPs identified in Stage 1 in the new cases and new controls. AIM 2: Identify SNPs that appear to interact with radiation exposure. Using the same two-stage design as for Aim 1, incorporate detailed information on radiation exposure to discover and validate the 6,000 most significant common SNPs that interact with radiation exposure and modify the risk of developing a second primary breast cancer. AIM 3: Using the entire WECARE Study population, determine whether genomic regions found to be associated with unilateral breast cancer as identified via independent GWA studies are also associated with risk of developing bilateral breast cancer, or radiation-induced breast cancer. AIM 4: Characterize genomic regions containing variants associated with bilateral breast cancer and/or radiation-induced breast cancer in a population-based case-control study design. The 10 most strongly implicated regions associated with potential causal SNPs identified in Aims 1, 2, or 3, will each be further characterized by re-sequencing to identify other variants for finer mapping of these regions. We will genotype putative disease associated and/or functional genetic variants in our entire study population of 3,707 women. Results from this study will help us understand genetic and environmental factors that influence susceptibility to breast cancer in particular and radiogenic cancers in general.

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Publications

Breast-cancer risk in families with mutations in PALB2.
Authors: Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkńs K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F, Tomiak E, Neuhausen SL, Teo ZL, Khan S, Aittomńki K, Moilanen JS, Turnbull C, Seal S, Mannermaa A, Kallioniemi A, Lindeman GJ, Buys SS, Andrulis IL, Radice P, Tondini C, Manoukian S, Toland AE, Miron P, Weitzel JN, Domchek SM, Poppe B, Claes KB, Yannoukakos D, Concannon P, Bernstein JL, James PA, Easton DF, Goldgar DE, Hopper JL, Rahman N, Peterlongo P, Nevanlinna H, King MC, Couch FJ, Southey MC, Winqvist R, Foulkes WD, Tischkowitz M
Source: N Engl J Med, 2014 Aug 7;371(6), p. 497-506.
PMID: 25099575
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Breast cancer after chest radiation therapy for childhood cancer.
Authors: Moskowitz CS, Chou JF, Wolden SL, Bernstein JL, Malhotra J, Novetsky Friedman D, Mubdi NZ, Leisenring WM, Stovall M, Hammond S, Smith SA, Henderson TO, Boice JD, Hudson MM, Diller LR, Bhatia S, Kenney LB, Neglia JP, Begg CB, Robison LL, Oeffinger KC
Source: J Clin Oncol, 2014 Jul 20;32(21), p. 2217-23.
EPub date: 2014 Apr 21.
PMID: 24752044
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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.
Authors: Brooks JD, Teraoka SN, Bernstein L, MellemkjŠr L, Malone KE, Lynch CF, Haile RW, Concannon P, Reiner AS, Duggan DJ, Schiermeyer K, WECARE Study Collaborative Group, Bernstein JL, Figueiredo JC
Source: Cancer Causes Control, 2013 Aug;24(8), p. 1605-14.
EPub date: 2013 Jun 18.
PMID: 23775025
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Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers: a WECARE study report.
Authors: Bernstein JL, Thomas DC, Shore RE, Robson M, Boice JD Jr, Stovall M, Andersson M, Bernstein L, Malone KE, Reiner AS, Lynch CF, Capanu M, Smith SA, Tellhed L, Teraoka SN, Begg CB, Olsen JH, Mellemkjaer L, Liang X, Diep AT, Borg A, Concannon P, Haile RW, WECARE Study Collaborative Group
Source: Eur J Cancer, 2013 Sep;49(14), p. 2979-85.
EPub date: 2013 May 21.
PMID: 23706288
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Risk of asynchronous contralateral breast cancer in noncarriers of BRCA1 and BRCA2 mutations with a family history of breast cancer: a report from the Women's Environmental Cancer and Radiation Epidemiology Study.
Authors: Reiner AS, John EM, Brooks JD, Lynch CF, Bernstein L, MellemkjŠr 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, Bernstein JL
Source: J Clin Oncol, 2013 Feb 1;31(4), p. 433-9.
EPub date: 2012 Dec 26.
PMID: 23269995
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Variation in genes related to obesity, weight, and weight change and risk of contralateral breast cancer in the WECARE Study population.
Authors: Brooks JD, Bernstein L, Teraoka SN, Knight JA, MellemkjŠr L, John EM, Malone KE, Reiner AS, Lynch CF, Concannon P, Haile RW, Bernstein JL, WECARE Study Collaborative Group
Source: Cancer Epidemiol Biomarkers Prev, 2012 Dec;21(12), p. 2261-7.
EPub date: 2012 Oct 2.
PMID: 23033454
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Reproductive status at first diagnosis influences risk of radiation-induced second primary contralateral breast cancer in the WECARE study.
Authors: Brooks JD, Boice JD Jr, Stovall M, Reiner AS, Bernstein L, John EM, Lynch CF, MellemkjŠr L, Knight JA, Thomas DC, Haile RW, Smith SA, Capanu M, Bernstein JL, Shore RE, WECARE Collaborative Group
Source: Int J Radiat Oncol Biol Phys, 2012 Nov 15;84(4), p. 917-24.
EPub date: 2012 Apr 6.
PMID: 22483700
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Rare germline mutations in PALB2 and breast cancer risk: a population-based study.
Authors: Tischkowitz M, Capanu M, Sabbaghian N, Li L, Liang X, VallÚe MP, Tavtigian SV, Concannon P, Foulkes WD, Bernstein L, WECARE Study Collaborative Group, Bernstein JL, Begg CB
Source: Hum Mutat, 2012 Apr;33(4), p. 674-80.
EPub date: 2012 Feb 15.
PMID: 22241545
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Incorporating prior biologic information for high-dimensional rare variant association studies.
Authors: Quintana MA, Schumacher FR, Casey G, Bernstein JL, Li L, Conti DV
Source: Hum Hered, 2012;74(3-4), p. 184-95.
EPub date: 2013 Apr 11.
PMID: 23594496
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Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study.
Authors: 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 JD Jr, Siniard A, Duggan D, Thomas DC, WECARE Study Collaborative Group, Concannon P
Source: Breast Cancer Res, 2011;13(6), p. R114.
EPub date: 2011 Nov 17.
PMID: 22087758
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Incorporating model uncertainty in detecting rare variants: the Bayesian risk index.
Authors: Quintana MA, Berstein JL, Thomas DC, Conti DV
Source: Genet Epidemiol, 2011 Nov;35(7), p. 638-49.
EPub date: 2011 Aug 26.
PMID: 22009789
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Variants in activators and downstream targets of ATM, radiation exposure, and contralateral breast cancer risk in the WECARE study.
Authors: Brooks JD, Teraoka SN, Reiner AS, Satagopan JM, Bernstein L, Thomas DC, Capanu M, Stovall M, Smith SA, Wei S, Shore RE, Boice JD Jr, Lynch CF, Mellemkjaer L, Malone KE, Liang X, Wecare Study Collaborative Group, Haile RW, Concannon P, Bernstein JL
Source: Hum Mutat, 2012 Jan;33(1), p. 158-64.
EPub date: 2011 Sep 29.
PMID: 21898661
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Body mass index and risk of second primary breast cancer: the WECARE Study.
Authors: Brooks JD, John EM, MellemkjŠr L, Reiner AS, Malone KE, Lynch CF, Figueiredo JC, Haile RW, Shore RE, WECARE Study Collaborative Group, Bernstein JL, Bernstein L
Source: Breast Cancer Res Treat, 2012 Jan;131(2), p. 571-80.
EPub date: 2011 Sep 3.
PMID: 21892703
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Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling.
Authors: Capanu M, Concannon P, Haile RW, Bernstein L, Malone KE, Lynch CF, Liang X, Teraoka SN, Diep AT, Thomas DC, Bernstein JL, WECARE Study Collaborative Group, Begg CB
Source: Genet Epidemiol, 2011 Jul;35(5), p. 389-97.
EPub date: 2011 Apr 25.
PMID: 21520273
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Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: potential modifying effect of BRCA1/BRCA2 mutation carrier status.
Authors: 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, Bernstein JL
Source: Breast Cancer Res Treat, 2011 Jun;127(3), p. 819-29.
EPub date: 2010 Dec 15.
PMID: 21161372
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Hierarchical modeling for estimating relative risks of rare genetic variants: properties of the pseudo-likelihood method.
Authors: Capanu M, Begg CB
Source: Biometrics, 2011 Jun;67(2), p. 371-80.
EPub date: 2010 Aug 5.
PMID: 20707869
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Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2.
Authors: 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
Source: J Clin Oncol, 2010 May 10;28(14), p. 2404-10.
EPub date: 2010 Apr 5.
PMID: 20368571
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Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study.
Authors: 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, WECARE Study Collaborative Group
Source: J Natl Cancer Inst, 2010 Apr 7;102(7), p. 475-83.
EPub date: 2010 Mar 19.
PMID: 20305132
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Adjuvant systemic therapy for breast cancer in BRCA1/BRCA2 mutation carriers in a population-based study of risk of contralateral breast cancer.
Authors: Reding KW, Bernstein JL, Langholz BM, Bernstein L, Haile RW, Begg CB, Lynch CF, Concannon P, Borg A, Teraoka SN, T÷rngren T, Diep A, Xue S, Bertelsen L, Liang X, Reiner AS, Capanu M, Malone KE, WECARE Collaborative Study Group
Source: Breast Cancer Res Treat, 2010 Sep;123(2), p. 491-8.
EPub date: 2010 Feb 5.
PMID: 20135344
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Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study.
Authors: Poynter JN, Langholz B, Largent J, Mellemkjaer L, Bernstein L, Malone KE, Lynch CF, Borg A, Concannon P, Teraoka SN, Xue S, Diep AT, T÷rngren T, Begg CB, Capanu M, Haile RW, WECARE Study Collaborative Group, Bernstein JL
Source: Cancer Causes Control, 2010 Jun;21(6), p. 839-46.
EPub date: 2010 Feb 4.
PMID: 20130978
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Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
Authors: Borg A, Haile RW, Malone KE, Capanu M, Diep A, T÷rngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, B°rresen-Dale AL, Bernstein JL
Source: Hum Mutat, 2010 Mar;31(3), p. E1200-40.
PMID: 20104584
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Oral contraceptives and postmenopausal hormones and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers and noncarriers: the WECARE Study.
Authors: Figueiredo JC, Haile RW, Bernstein L, Malone KE, Largent J, Langholz B, Lynch CF, Bertelsen L, Capanu M, Concannon P, Borg A, B°rresen-Dale AL, Diep A, Teraoka S, Torngren T, Xue S, Bernstein JL
Source: Breast Cancer Res Treat, 2010 Feb;120(1), p. 175-83.
EPub date: 2009 Jul 14.
PMID: 19597986
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