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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

Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers.
Authors: Park DJ, Tao K, Le Calvez-Kelm F, Nguyen-Dumont T, Robinot N, Hammet F, Odefrey F, Tsimiklis H, Teo ZL, Thingholm LB, Young EL, Voegele C, Lonie A, Pope BJ, Roane TC, Bell R, Hu H, Shankaracharya, Huff CD, Ellis J, Li J, Makunin IV, John EM, Andrulis IL, Terry MB, Daly M, Buys SS, Snyder C, Lynch HT, Devilee P, Giles GG, Hopper JL, Feng BJ, Lesueur F, Tavtigian SV, Southey MC, Goldgar DE
Source: Cancer Discov, 2014 Jul;4(7), p. 804-15.
EPub date: 2014 May 2.
PMID: 25050558
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Growing recognition of the role for rare missense substitutions in breast cancer susceptibility.
Authors: Tavtigian SV, Chenevix-Trench G
Source: Biomark Med, 2014 Apr;8(4), p. 589-603.
PMID: 24796624
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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 MP, Byrnes G, Registry BC, Hopper JL, Southey MC, Andrulis IL, John EM, Tavtigian SV, Lesueur F
Source: PLoS One, 2012;7(12), p. e52374.
EPub date: 2012 Dec 27.
PMID: 23300655
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Rare mutations in XRCC2 increase the risk of breast cancer.
Authors: Park DJ, Lesueur F, Nguyen-Dumont T, Pertesi M, Odefrey F, Hammet F, Neuhausen SL, John EM, Andrulis IL, Terry MB, Daly M, Buys S, Le Calvez-Kelm F, Lonie A, Pope BJ, Tsimiklis H, Voegele C, Hilbers FM, Hoogerbrugge N, Barroso A, Osorio A, Breast Cancer Family Registry, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Giles GG, Devilee P, Benitez J, Hopper JL, Tavtigian SV, Goldgar DE, Southey MC
Source: Am J Hum Genet, 2012 Apr 6;90(4), p. 734-9.
EPub date: 2012 Mar 29.
PMID: 22464251
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Rare variants in the ATM gene and risk of breast cancer.
Authors: Goldgar DE, Healey S, Dowty JG, Da Silva L, Chen X, Spurdle AB, Terry MB, Daly MJ, Buys SM, Southey MC, Andrulis I, John EM, BCFR, kConFab, Khanna KK, Hopper JL, Oefner PJ, Lakhani S, Chenevix-Trench G
Source: Breast Cancer Res, 2011 Jul 25;13(4), p. R73.
EPub date: 2011 Jul 25.
PMID: 21787400
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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 LP, 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 MC, Tavtigian SV, Lesueur F
Source: BMC Med Genomics, 2011 May 11;4, p. 39.
EPub date: 2011 May 11.
PMID: 21569354
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Tests of association for rare variants: case control mutation screening.
Authors: Tavtigian SV, Hashibe M, Thomas A
Source: Nat Rev Genet, 2011 Mar;12(3), p. 224.
EPub date: 2011 Feb 1.
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, Nguyen-Dumont T, Thomas A, Byrnes GB, Breast Cancer Family Registry, Hopper JL, Southey MC, Andrulis IL, John EM, Tavtigian SV
Source: Breast Cancer Res, 2011 Jan 18;13(1), p. R6.
EPub date: 2011 Jan 18.
PMID: 21244692
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Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.
Authors: Tavtigian SV, Oefner PJ, Babikyan D, Hartmann A, Healey S, Le Calvez-Kelm F, Lesueur F, Byrnes GB, Chuang SC, Forey N, Feuchtinger C, Gioia L, Hall J, Hashibe M, Herte B, McKay-Chopin S, Thomas A, Vallée MP, Voegele C, Webb PM, Whiteman DC, Australian Cancer Study, Breast Cancer Family Registries (BCFR), Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer (kConFab), Sangrajrang S, Hopper JL, Southey MC, Andrulis IL, John EM, Chenevix-Trench G
Source: Am J Hum Genet, 2009 Oct;85(4), p. 427-46.
EPub date: 2009 Sep 24.
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 FL, Forey N, McKay-Chopin S, Garritano S, Gioia-Patricola L, De Silva D, Weigel R, Sangrajrang S, Lesueur F, Tavtigian SV, Breast Cancer Family Registries (BCFR), Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)
Source: Hum Mutat, 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 AM, Healey CS, Baynes C, Maia AT, Scollen S, Vega A, Rodríguez R, Barbosa-Morais NL, Ponder BA, SEARCH, Low YL, Bingham S, EPIC, Haiman CA, Le Marchand L, MEC, Broeks A, Schmidt MK, ABCS, Hopper J, Southey M, ABCFS, Beckmann MW, Fasching PA, BBCC, Peto J, Johnson N, BBCS, Bojesen SE, Nordestgaard B, CGPS, Milne RL, Benitez J, CNIO-BCS, Hamann U, Ko Y, GENICA, Schmutzler RK, Burwinkel B, GC-HBOC, Schürmann P, Dörk T, HABCS, Heikkinen T, Nevanlinna H, HEBCS, Lindblom A, Margolin S, KARBAC, Mannermaa A, Kosma VM, KBCS, Chen X, Spurdle A, kConFab and the AOCS Management Group, Change-Claude J, Flesch-Janys D, MARIE, Couch FJ, Olson JE, for MCBCS, Severi G, Baglietto L, MCCS, Børresen-Dale AL, Kristensen V, NBCS, Hunter DJ, Hankinson SE, NHS, Devilee P, Vreeswijk M, ORIGO, Lissowska J, Brinton L, PBCS, Liu J, Hall P, SASBAC, Kang D, Yoo KY, SEBCS, Shen CY, Yu JC, TWBCS, Anton-Culver H, Ziogoas A, UCIBCS, Sigurdson A, Struewing J, USRTS, Easton DF, Garcia-Closas M, Humphreys MK, Morrison J, Pharoah PD, Pooley KA, Chenevix-Trench G, BCAC
Source: Hum Mol Genet, 2009 Mar 15;18(6), p. 1131-9.
EPub date: 2009 Jan 6.
PMID: 19126777
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Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications.
Authors: Tavtigian SV, Byrnes GB, Goldgar DE, Thomas A
Source: Hum Mutat, 2008 Nov;29(11), p. 1342-54.
PMID: 18951461
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