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

Grant Number: 5R01CA121245-05 Interpret this number
Primary Investigator: Tavtigian, Sean
Organization: University Of Utah
Project Title: Common and Rare Sequence Variants in Breast Cancer Risk
Fiscal Year: 2011
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Abstract

DESCRIPTION (provided by applicant): Combining data from segregation analyses and mutation screening studies, the established breast cancer susceptibility genes are responsible for an estimated 20%-25% of the genetic component of this disease. The genes and/or sequence variants responsible for the remaining genetic component of breast cancer risk have yet to be identified. Most of the current enthusiasm for SNPs and haplotype mapping are predicated on the assumption that common modest risk variants are most important. However, few candidate associations between common SNPs and breast cancer risk have been independently reproduced. Thus the central question of this study: What is the relative contribution of common (usually modest-risk) sequence variants vs. rare (potentially higher-risk) sequence variants to the genetic attributable fraction of breast cancer? U Using an ethnically diverse series of 1,250 genetically high-risk breast cancer cases and 1,250 frequency-matched population controls, we propose a novel study designed to make a direct comparison between the common disease/ common variant and common disease/ rare variant models of genetic susceptibility. The study has two arms. In the first, we will genotype the cases and controls with all of the common- sequence variants that are known, or are found over the course of this study by the breast cancer genetics research community, to predict increased risk of breast cancer. In the second arm, we will mutation screen the open reading frames of strong candidate susceptibility genes in both the cases and the controls. Analysis of the genotype and mutation screening data should provide an answer to the central study question. Our focus on early onset and familial cases will substantially increase power to detect risk conferred by deleterious sequence variants as compared to a study of similar size without these criteria, fl Results from this study are relevant to public health in three ways: (1) This study will provide a hypothesis test of genes, and mutations in them, that appear to confer moderately to dramatically increased risk of breast cancer. Measuring risk due to mutations in these genes is a key step that lies between initial indications that the gene plays a role in breast cancer susceptibility and bringing the gene into the clinical practice of cancer genetics. (2) Results from this study will bear on the future direction of clinical cancer genetics. The relative contribution that moderate risk versus modest risk sequence variants make to the attributable risk of breast cancer will have an impact on how the genetic information enters clinical practice. (3) Analysis of the genotype and mutation screening data will provide a comparison of risk attributable to the common variant and rare variant genetic models of cancer susceptibility. This is a question of major current interest and importance within the genetics research community. If we observe that the rare sequence variants account for as much or more risk than do common SNPs, it may be necessary to expand mutation screening from the realm of genetic epidemiology/ family studies into larger scale population-based studies.

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Publications

Multigene Testing Of Moderate-risk Genes: Be Mindful Of The Missense
Authors: Young E.L. , Feng B.J. , Stark A.W. , Damiola F. , Durand G. , Forey N. , Francy T.C. , Gammon A. , Kohlmann W.K. , Kaphingst K.A. , et al. .
Source: Journal Of Medical Genetics, 2016 Jun; 53(6), p. 366-76.
PMID: 26787654
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No Evidence That Protein Truncating Variants In Brip1 Are Associated With Breast Cancer Risk: Implications For Gene Panel Testing
Authors: Easton D.F. , Lesueur F. , Decker B. , Michailidou K. , Li J. , Allen J. , Luccarini C. , Pooley K.A. , Shah M. , Bolla M.K. , et al. .
Source: Journal Of Medical Genetics, 2016-02-26 00:00:00.0; , .
PMID: 26921362
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Rare Mutations In Rint1 Predispose Carriers To Breast And Lynch Syndrome-spectrum Cancers
Authors: Park D.J. , Tao K. , Le Calvez-Kelm F. , Nguyen-Dumont T. , Robinot N. , Hammet F. , Odefrey F. , Tsimiklis H. , Teo Z.L. , Thingholm L.B. , et al. .
Source: Cancer Discovery, 2014 Jul; 4(7), p. 804-15.
PMID: 25050558
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Growing Recognition Of The Role For rare Missense Substitutions In Breast Cancer Susceptibility
Authors: Tavtigian S.V. , Chenevix-Trench G. .
Source: Biomarkers In Medicine, 2014; 8(4), p. 589-603.
PMID: 24796624
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Rare Key Functional Domain Missense Substitutions In Mre11a, Rad50, And Nbn Contribute To Breast Cancer Susceptibility: Results From A Breast Cancer Family Registry Case-control Mutation-screening Study
Authors: Damiola F. , Pertesi M. , Oliver J. , Le Calvez-Kelm F. , Voegele C. , Young E.L. , Robinot N. , Forey N. , Durand G. , Vallée M.P. , et al. .
Source: Breast Cancer Research : Bcr, 2014; 16(3), p. R58.
PMID: 24894818
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Rare Mutations In Xrcc2 Increase The Risk Of Breast Cancer
Authors: Park D.J. , Lesueur F. , Nguyen-Dumont T. , Pertesi M. , Odefrey F. , Hammet F. , Neuhausen S.L. , John E.M. , Andrulis I.L. , Terry M.B. , et al. .
Source: American Journal Of Human Genetics, 2012-04-06 00:00:00.0; 90(4), p. 734-9.
PMID: 22464251
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Rad51 And Breast Cancer Susceptibility: No Evidence For Rare Variant Association In The Breast Cancer Family Registry Study
Authors: Le Calvez-Kelm F. , Oliver J. , Damiola F. , Forey N. , Robinot N. , Durand G. , Voegele C. , Vallée M.P. , Byrnes G. , Registry B.C. , et al. .
Source: Plos One, 2012; 7(12), p. e52374.
PMID: 23300655
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Tests Of Association For Rare Variants: Case Control Mutation Screening
Authors: Tavtigian S.V. , Hashibe M. , Thomas A. .
Source: Nature Reviews. Genetics, 2011 Mar; 12(3), p. 224.
PMID: 21283087
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Rare, Evolutionarily Unlikely Missense Substitutions In Chek2 Contribute To Breast Cancer Susceptibility: Results From A Breast Cancer Family Registry Case-control Mutation-screening Study
Authors: Le Calvez-Kelm F. , Lesueur F. , Damiola F. , Vallée M. , Voegele C. , Babikyan D. , Durand G. , Forey N. , McKay-Chopin S. , Robinot N. , et al. .
Source: Breast Cancer Research : Bcr, 2011; 13(1), p. R6.
PMID: 21244692
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Detecting Differential Allelic Expression Using High-resolution Melting Curve Analysis: Application To The Breast Cancer Susceptibility Gene Chek2
Authors: Nguyen-Dumont T. , Jordheim L.P. , Michelon J. , Forey N. , McKay-Chopin S. , Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer , Sinilnikova O. , Le Calvez-Kelm F. , Southey M.C. , Tavtigian S.V. , et al. .
Source: Bmc Medical Genomics, 2011; 4, p. 39.
PMID: 21569354
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Rare Variants In The Atm Gene And Risk Of Breast Cancer
Authors: Goldgar D.E. , Healey S. , Dowty J.G. , Da Silva L. , Chen X. , Spurdle A.B. , Terry M.B. , Daly M.J. , Buys S.M. , Southey M.C. , et al. .
Source: Breast Cancer Research : Bcr, 2011; 13(4), p. R73.
PMID: 21787400
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Rare, Evolutionarily Unlikely Missense Substitutions In Atm Confer Increased Risk Of Breast Cancer
Authors: Tavtigian S.V. , Oefner P.J. , Babikyan D. , Hartmann A. , Healey S. , Le Calvez-Kelm F. , Lesueur F. , Byrnes G.B. , Chuang S.C. , Forey N. , et al. .
Source: American Journal Of Human Genetics, 2009 Oct; 85(4), p. 427-46.
PMID: 19781682
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Description And Validation Of High-throughput Simultaneous Genotyping And Mutation Scanning By High-resolution Melting Curve Analysis
Authors: Nguyen-Dumont T. , Calvez-Kelm F.L. , Forey N. , McKay-Chopin S. , Garritano S. , Gioia-Patricola L. , De Silva D. , Weigel R. , Sangrajrang S. , Lesueur F. , et al. .
Source: Human Mutation, 2009 Jun; 30(6), p. 884-90.
PMID: 19347964
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Association Of Esr1 Gene Tagging Snps With Breast Cancer Risk
Authors: Dunning A.M. , Healey C.S. , Baynes C. , Maia A.T. , Scollen S. , Vega A. , Rodríguez R. , Barbosa-Morais N.L. , Ponder B.A. , SEARCH , et al. .
Source: Human Molecular Genetics, 2009-03-15 00:00:00.0; 18(6), p. 1131-9.
PMID: 19126777
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Classification Of Rare Missense Substitutions, Using Risk Surfaces, With Genetic- And Molecular-epidemiology Applications
Authors: Tavtigian S.V. , Byrnes G.B. , Goldgar D.E. , Thomas A. .
Source: Human Mutation, 2008 Nov; 29(11), p. 1342-54.
PMID: 18951461
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