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Grant Details

Grant Number: 5R01CA114236-04 Interpret this number
Primary Investigator: Bernstein, Jonine
Organization: Sloan-Kettering Inst Can Research
Project Title: Breast Cancer, Radiation and the Atm-Chek2 Pathway
Fiscal Year: 2008
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Abstract

DESCRIPTION (provided by applicant): All of the genes known to be associated with increased susceptibility to breast cancer function within a common biochemical pathway involved in signaling the presence of and responding to DNA double-strand breaks. Upon exposure to ionizing radiation (IR), ATM phosphorylates a large number of downstream targets, including the protein products of BRCA1 and CHEK2, in which specific mutations have been shown to predispose to breast cancer. Signaling between ATM and Chek2 involves at least five other proteins, p53 binding protein (53BP1), and MDC1, Mre11, RadSO, and Nbs1 (the latter three forming the MRN complex). To delineate the roles of radiation exposure and genetic predisposition in the etiology of breast cancer, we propose a case-control association study to examine the interaction of IR exposure with genetic variation in these genes in a population-based sample of young women with bilateral and unilateral breast cancer. Our study hypothesis is that the incidence of contralateral breast cancer will be increased among women who carry mutant alleles, alone, or in combination with one another, and who received radiation therapy as part of their treatment for first primary breast cancer. To carry out the current proposal, we will use the 2100 cases and controls from our multi-center WECARE Study and access the already established comprehensive data and biorepository that includes, for all study participants, epidemiologic data, biological specimens, treatment records, radiation dosimetry, and ATM, BRCA1 and BRCA2 mutation carrier status. Our specific aims are: Aim #1. Identify haplotype block structures and tagging SNPs for CHEK2, TP53BP1, MDC1, MRE11, RAD50 and NBS1. Aim #2. Genotype all 2100 WECARE Study participants (700 triplets) using SNPs identified in Aim #1 and selected based on haplotype analysis of sequenced samples. Aim #3. Conduct a population-based case-control association study of 6 genes involved in the ATM-CHEK2 pathway to determine whether they are associated with an increased risk of radiation-induced contralateral breast cancer.

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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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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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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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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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Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study.
Authors: Mellemkjaer L, Dahl C, Olsen JH, Bertelsen L, Guldberg P, Christensen J, B°rresen-Dale AL, Stovall M, Langholz B, Bernstein L, Lynch CF, Malone KE, Haile RW, Andersson M, Thomas DC, Concannon P, Capanu M, Boice JD Jr, WECARE Study Collaborative Group, Bernstein JL
Source: Br J Cancer, 2008 Feb 26;98(4), p. 728-33.
EPub date: 2008 Feb 5.
PMID: 18253122
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Effect of systemic adjuvant treatment on risk for contralateral breast cancer in the Women's Environment, Cancer and Radiation Epidemiology Study.
Authors: 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
Source: J Natl Cancer Inst, 2008 Jan 2;100(1), p. 32-40.
EPub date: 2007 Dec 25.
PMID: 18159070
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The CHEK2*1100delC allelic variant and risk of breast cancer: screening results from the Breast Cancer Family Registry.
Authors: Bernstein JL, Teraoka SN, John EM, Andrulis IL, Knight JA, Lapinski R, Olson ER, Wolitzer AL, Seminara D, Whittemore AS, Concannon P
Source: Cancer Epidemiol Biomarkers Prev, 2006 Feb;15(2), p. 348-52.
PMID: 16492927
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