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National Institutes of Health: National Cancer Institute: Division of Cancer Control and Population Sciences
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

The Chek2*1100delc Allelic Variant And Risk Of Breast Cancer: Screening Results From The Breast Cancer Family Registry
Authors: Bernstein J.L. , Teraoka S.N. , John E.M. , Andrulis I.L. , Knight J.A. , Lapinski R. , Olson E.R. , Wolitzer A.L. , Seminara D. , Whittemore A.S. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2006 Feb; 15(2), p. 348-52.
PMID: 16492927
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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 J.H. , Mellemkjaer L. , Haile R.W. , Lynch C.F. , Malone K.E. , Anton-Culver H. , Christensen J. , Langholz B. , et al. .
Source: Journal Of The National Cancer Institute, 2008-01-02 00:00:00.0; 100(1), p. 32-40.
PMID: 18159070
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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 J.H. , Bertelsen L. , Guldberg P. , Christensen J. , B°rresen-Dale A.L. , Stovall M. , Langholz B. , Bernstein L. , et al. .
Source: British Journal Of Cancer, 2008-02-26 00:00:00.0; 98(4), p. 728-33.
PMID: 18253122
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Body Mass Index And Risk Of Second Primary Breast Cancer: The Wecare Study
Authors: Brooks J.D. , John E.M. , MellemkjŠr L. , Reiner A.S. , Malone K.E. , Lynch C.F. , Figueiredo J.C. , Haile R.W. , Shore R.E. , WECARE Study Collaborative Group , et al. .
Source: Breast Cancer Research And Treatment, 2012 Jan; 131(2), p. 571-80.
PMID: 21892703
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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 J.D. , Teraoka S.N. , Reiner A.S. , Satagopan J.M. , Bernstein L. , Thomas D.C. , Capanu M. , Stovall M. , Smith S.A. , Wei S. , et al. .
Source: Human Mutation, 2012 Jan; 33(1), p. 158-64.
PMID: 21898661
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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 S.N. , Bernstein J.L. , Reiner A.S. , Haile R.W. , Bernstein L. , Lynch C.F. , Malone K.E. , Stovall M. , Capanu M. , Liang X. , et al. .
Source: Breast Cancer Research : Bcr, 2011; 13(6), p. R114.
PMID: 22087758
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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 M.P. , Tavtigian S.V. , Concannon P. , Foulkes W.D. , Bernstein L. , et al. .
Source: Human Mutation, 2012 Apr; 33(4), p. 674-80.
PMID: 22241545
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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 J.D. , Boice J.D. , Stovall M. , Reiner A.S. , Bernstein L. , John E.M. , Lynch C.F. , MellemkjŠr L. , Knight J.A. , Thomas D.C. , et al. .
Source: International Journal Of Radiation Oncology, Biology, Physics, 2012-11-15 00:00:00.0; 84(4), p. 917-24.
PMID: 22483700
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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 J.D. , Bernstein L. , Teraoka S.N. , Knight J.A. , MellemkjŠr L. , John E.M. , Malone K.E. , Reiner A.S. , Lynch C.F. , Concannon P. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2012 Dec; 21(12), p. 2261-7.
PMID: 23033454
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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 A.S. , John E.M. , Brooks J.D. , Lynch C.F. , Bernstein L. , MellemkjŠr L. , Malone K.E. , Knight J.A. , Capanu M. , Teraoka S.N. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2013-02-01 00:00:00.0; 31(4), p. 433-9.
PMID: 23269995
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Contralateral Breast Cancer After Radiotherapy Among Brca1 And Brca2 Mutation Carriers: A Wecare Study Report
Authors: Bernstein J.L. , Thomas D.C. , Shore R.E. , Robson M. , Boice J.D. , Stovall M. , Andersson M. , Bernstein L. , Malone K.E. , Reiner A.S. , et al. .
Source: European Journal Of Cancer (oxford, England : 1990), 2013 Sep; 49(14), p. 2979-85.
PMID: 23706288
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Breast-cancer Risk In Families With Mutations In Palb2
Authors: Antoniou A.C. , Casadei S. , Heikkinen T. , Barrowdale D. , Pylkńs K. , Roberts J. , Lee A. , Subramanian D. , De Leeneer K. , Fostira F. , et al. .
Source: The New England Journal Of Medicine, 2014-08-07 00:00:00.0; 371(6), p. 497-506.
PMID: 25099575
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Phosphorylation Of Glutathione S-transferase P1 (gstp1) By Epidermal Growth Factor Receptor (egfr) Promotes Formation Of The Gstp1-c-jun N-terminal Kinase (jnk) Complex And Suppresses Jnk Downstream Signaling And Apoptosis In Brain Tumor Cells
Authors: Okamura T. , Antoun G. , Keir S.T. , Friedman H. , Bigner D.D. , Ali-Osman F. .
Source: The Journal Of Biological Chemistry, 2015-12-25 00:00:00.0; 290(52), p. 30866-78.
PMID: 26429914
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