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Grant Details

Grant Number: 5R01CA192393-05 Interpret this number
Primary Investigator: Couch, Fergus
Organization: Mayo Clinic Rochester
Project Title: Risk and Penetrance of Mutations From Breast Cancer Testing Panels.
Fiscal Year: 2018
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Abstract

DESCRIPTION (provided by applicant): Breast cancer is one of the most common cancers in the US. Approximately 15% to 20% of cases exhibit a family history of the disease suggesting a strong heritable component. Susceptibility to breast cancer is associated with high-penetrance germline mutations in BRCA1, BRCA2, PTEN, STK11, CDH1, and TP53. In addition, inherited inactivating mutations in several other genes have been associated with familial breast cancer. These include ATM, CHEK2, PALB2, BRIP1, BARD1, RAD51C, RAD51D, XRCC2, NBN, RAD50, and MRE11A. While inactivating mutations in ATM and CHEK2 have been associated with moderate 3 to 7-fold increased risk of breast cancer with lifetime risks of between 20% and 50%, these risk estimates are imprecise and little is known about the risk of breast and other cancers associated with inactivating mutations in the other predisposition genes. Clinical genetic testing for all of these high and moderate risk predisposition genes is now available. Many women, with personal and family history of breast, ovarian or other cancers, are pursuing testing for mutations with these panels, which has seen an upsurge in demand in response to 'Angelina's story'. Initial data suggest that ~10% of panel tests identify truncating mutations and 20% yield variants of uncertain significance (VUS) in the form of missense and intronic changes of undefined clinical relevance in the known predisposition genes. Although potentially useful for establishing the etiology of breast cancer in a patient's family, there remain significant limitatins in the clinical interpretation of the results from the panel testing. In particular, the age-relate risk of breast and other cancers associated with mutations in the genes are largely undefined. Furthermore, clear medical management recommendations for mutation carriers have not been developed. Thus, the results of these tests can lead to confusion and uninformed medical decisions that can result in significant harm. We propose to use high-throughput mutation screening of known breast cancer predisposition genes in breast cancer case-control studies and high-risk breast cancer families to establish the risks of breast and other cancers associated with deleterious mutations in these genes as follows: Aim 1) Establish the risk of breast cancer in the general population associated with mutations in known predisposition genes using large cohort-based case-control studies; Aim 2) Define the penetrance of cancers associated with inactivating mutations in panel-based predisposition genes through breast cancer family studies; Aim 3) Determine the clinical relevance of VUS in the known predisposition genes. At the conclusion of the study, we expect to establish risk estimates associated with deleterious mutations in the genes for the general population and breast cancer families, leading to much improved risk assessment for mutation carriers. In addition, we expect to establish the clinical relevance of many VUS in the known predisposition genes. The results of this study will also provide the necessary data to establish standard of care medical management recommendations for carriers of deleterious mutations in moderate penetrance genes, a critical unmet need.

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Publications

Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.
Authors: Hu C. , Hart S.N. , Polley E.C. , Gnanaolivu R. , Shimelis H. , Lee K.Y. , Lilyquist J. , Na J. , Moore R. , Antwi S.O. , et al. .
Source: Jama, 2018-06-19 00:00:00.0; 319(23), p. 2401-2409.
PMID: 29922827
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Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models.
Authors: Hart S.N. , Hoskin T. , Shimelis H. , Moore R.M. , Feng B. , Thomas A. , Lindor N.M. , Polley E.C. , Goldgar D.E. , Iversen E. , et al. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2018-06-08 00:00:00.0; , .
EPub date: 2018-06-08 00:00:00.0.
PMID: 29884841
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BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study.
Authors: Fasching P.A. , Loibl S. , Hu C. , Hart S.N. , Shimelis H. , Moore R. , Schem C. , Tesch H. , Untch M. , Hilfrich J. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2018-05-23 00:00:00.0; , p. JCO2017772285.
EPub date: 2018-05-23 00:00:00.0.
PMID: 29791287
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The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.
Authors: Colombo M. , Lòpez-Perolio I. , Meeks H.D. , Caleca L. , Parsons M.T. , Li H. , De Vecchi G. , Tudini E. , Foglia C. , Mondini P. , et al. .
Source: Human Mutation, 2018 May; 39(5), p. 729-741.
EPub date: 2018-04-06 00:00:00.0.
PMID: 29460995
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E-cadherin breast tumor expression, risk factors and survival: Pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium.
Authors: Horne H.N. , Oh H. , Sherman M.E. , Palakal M. , Hewitt S.M. , Schmidt M.K. , Milne R.L. , Hardisson D. , Benitez J. , Blomqvist C. , et al. .
Source: Scientific Reports, 2018-04-26 00:00:00.0; 8(1), p. 6574.
EPub date: 2018-04-26 00:00:00.0.
PMID: 29700408
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Joint associations of a polygenic risk score and environmental risk factors for breast cancer in the Breast Cancer Association Consortium.
Authors: Rudolph A. , Song M. , Brook M.N. , Milne R.L. , Mavaddat N. , Michailidou K. , Bolla M.K. , Wang Q. , Dennis J. , Wilcox A.N. , et al. .
Source: International Journal Of Epidemiology, 2018-04-01 00:00:00.0; 47(2), p. 526-536.
PMID: 29315403
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Common Genetic Variation and Breast Cancer Risk-Past, Present, and Future.
Authors: Lilyquist J. , Ruddy K.J. , Vachon C.M. , Couch F.J. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2018 Apr; 27(4), p. 380-394.
EPub date: 2018-01-30 00:00:00.0.
PMID: 29382703
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The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers.
Authors: Weigelt B. , Bi R. , Kumar R. , Blecua P. , Mandelker D.L. , Geyer F.C. , Pareja F. , James P.A. , kConFab Investigators , Couch F.J. , et al. .
Source: Journal Of The National Cancer Institute, 2018-02-28 00:00:00.0; , .
EPub date: 2018-02-28 00:00:00.0.
PMID: 29506079
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Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.
Authors: Guidugli L. , Shimelis H. , Masica D.L. , Pankratz V.S. , Lipton G.B. , Singh N. , Hu C. , Monteiro A.N.A. , Lindor N.M. , Goldgar D.E. , et al. .
Source: American Journal Of Human Genetics, 2018-01-17 00:00:00.0; , .
EPub date: 2018-01-17 00:00:00.0.
PMID: 29394989
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Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.
Authors: Milne R.L. , Kuchenbaecker K.B. , Michailidou K. , Beesley J. , Kar S. , Lindström S. , Hui S. , Lemaçon A. , Soucy P. , Dennis J. , et al. .
Source: Nature Genetics, 2017 Dec; 49(12), p. 1767-1778.
EPub date: 2017-10-23 00:00:00.0.
PMID: 29058716
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- a novel candidate breast cancer susceptibility locus on 6q14.1.
Authors: Jiao X. , Aravidis C. , Marikkannu R. , Rantala J. , Picelli S. , Adamovic T. , Liu T. , Maguire P. , Kremeyer B. , Luo L. , et al. .
Source: Oncotarget, 2017-11-28 00:00:00.0; 8(61), p. 102769-102782.
EPub date: 2017-10-12 00:00:00.0.
PMID: 29262523
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Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study.
Authors: Brouckaert O. , Rudolph A. , Laenen A. , Keeman R. , Bolla M.K. , Wang Q. , Soubry A. , Wildiers H. , Andrulis I.L. , Arndt V. , et al. .
Source: Breast Cancer Research : Bcr, 2017-11-07 00:00:00.0; 19(1), p. 119.
EPub date: 2017-11-07 00:00:00.0.
PMID: 29116004
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Association analysis identifies 65 new breast cancer risk loci.
Authors: Michailidou K. , Lindström S. , Dennis J. , Beesley J. , Hui S. , Kar S. , Lemaçon A. , Soucy P. , Glubb D. , Rostamianfar A. , et al. .
Source: Nature, 2017-11-02 00:00:00.0; 551(7678), p. 92-94.
EPub date: 2017-10-23 00:00:00.0.
PMID: 29059683
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Gene-environment interactions involving functional variants: Results from the Breast Cancer Association Consortium.
Authors: Barrdahl M. , Rudolph A. , Hopper J.L. , Southey M.C. , Broeks A. , Fasching P.A. , Beckmann M.W. , Gago-Dominguez M. , Castelao J.E. , Guénel P. , et al. .
Source: International Journal Of Cancer, 2017-11-01 00:00:00.0; 141(9), p. 1830-1840.
EPub date: 2017-08-11 00:00:00.0.
PMID: 28670784
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Impact of histopathology, tumor-infiltrating lymphocytes, and adjuvant chemotherapy on prognosis of triple-negative breast cancer.
Authors: Leon-Ferre R.A. , Polley M.Y. , Liu H. , Gilbert J.A. , Cafourek V. , Hillman D.W. , Elkhanany A. , Akinhanmi M. , Lilyquist J. , Thomas A. , et al. .
Source: Breast Cancer Research And Treatment, 2017-09-14 00:00:00.0; , .
EPub date: 2017-09-14 00:00:00.0.
PMID: 28913760
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Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.
Authors: Day F.R. , Thompson D.J. , Helgason H. , Chasman D.I. , Finucane H. , Sulem P. , Ruth K.S. , Whalen S. , Sarkar A.K. , Albrecht E. , et al. .
Source: Nature Genetics, 2017 Jun; 49(6), p. 834-841.
EPub date: 2017-04-24 00:00:00.0.
PMID: 28436984
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Associations Between Cancer Predisposition Testing Panel Genes And Breast Cancer
Authors: Couch F.J. , Shimelis H. , Hu C. , Hart S.N. , Polley E.C. , Na J. , Hallberg E. , Moore R. , Thomas A. , Lilyquist J. , et al. .
Source: Jama Oncology, 2017-04-13 00:00:00.0; , .
PMID: 28418444
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Evaluation Of Copy-number Variants As Modifiers Of Breast And Ovarian Cancer Risk For Brca1 Pathogenic Variant Carriers
Authors: Walker L.C. , Marquart L. , Pearson J.F. , Wiggins G.A. , O'Mara T.A. , Parsons M.T. , BCFR , Barrowdale D. , McGuffog L. , Dennis J. , et al. .
Source: European Journal Of Human Genetics : Ejhg, 2017 Apr; 25(4), p. 432-438.
PMID: 28145423
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TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.
Authors: Fagerholm R. , Khan S. , Schmidt M.K. , García-Closas M. , Heikkilä P. , Saarela J. , Beesley J. , Jamshidi M. , Aittomäki K. , Liu J. , et al. .
Source: Oncotarget, 2017-03-14 00:00:00.0; 8(11), p. 18381-18398.
PMID: 28179588
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Brca2 Hypomorphic Missense Variants Confer Moderate Risks Of Breast Cancer
Authors: Shimelis H. , Mesman R.L. , Von Nicolai C. , Ehlen A. , Guidugli L. , Martin C. , Calleja F.M. , Meeks H. , Hallberg E. , Hinton J. , et al. .
Source: Cancer Research, 2017-03-10 00:00:00.0; , .
PMID: 28283652
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The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers.
Authors: Amos C.I. , Dennis J. , Wang Z. , Byun J. , Schumacher F.R. , Gayther S.A. , Casey G. , Hunter D.J. , Sellers T.A. , Gruber S.B. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2017 Jan; 26(1), p. 126-135.
PMID: 27697780
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The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk.
Authors: Slavin T.P. , Maxwell K.N. , Lilyquist J. , Vijai J. , Neuhausen S.L. , Hart S.N. , Ravichandran V. , Thomas T. , Maria A. , Villano D. , et al. .
Source: Npj Breast Cancer, 2017; 3, p. 22.
EPub date: 2017-06-09 00:00:00.0.
PMID: 28649662
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Male Breast Cancer In A Multi-gene Panel Testing Cohort: Insights And Unexpected Results
Authors: Pritzlaff M. , Summerour P. , McFarland R. , Li S. , Reineke P. , Dolinsky J.S. , Goldgar D.E. , Shimelis H. , Couch F.J. , Chao E.C. , et al. .
Source: Breast Cancer Research And Treatment, 2016-12-22 00:00:00.0; , .
PMID: 28008555
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Perch: A Unified Framework For Disease Gene Prioritization
Authors: Feng B.J. .
Source: Human Mutation, 2016-12-19 00:00:00.0; , .
PMID: 27995669
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Association Of Breast Cancer Risk With Genetic Variants Showing Differential Allelic Expression: Identification Of A Novel Breast Cancer Susceptibility Locus At 4q21
Authors: Hamdi Y. , Soucy P. , Adoue V. , Michailidou K. , Canisius S. , Lemaçon A. , Droit A. , Andrulis I.L. , Anton-Culver H. , Arndt V. , et al. .
Source: Oncotarget, 2016-12-06 00:00:00.0; 7(49), p. 80140-80163.
PMID: 27792995
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Rs2735383, Located At A Microrna Binding Site In The 3'utr Of Nbs1, Is Not Associated With Breast Cancer Risk
Authors: Liu J. , Lon¿ar I. , Collée J.M. , Bolla M.K. , Dennis J. , Michailidou K. , Wang Q. , Andrulis I.L. , Barile M. , Beckmann M.W. , et al. .
Source: Scientific Reports, 2016-11-15 00:00:00.0; 6, p. 36874.
PMID: 27845421
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Association Of Breast Cancer Risk In Brca1 And Brca2 Mutation Carriers With Genetic Variants Showing Differential Allelic Expression: Identification Of A Modifier Of Breast Cancer Risk At Locus 11q22.3
Authors: Hamdi Y. , Soucy P. , Kuchenbaeker K.B. , Pastinen T. , Droit A. , Lemaçon A. , Adlard J. , Aittomäki K. , Andrulis I.L. , Arason A. , et al. .
Source: Breast Cancer Research And Treatment, 2016-10-28 00:00:00.0; , .
PMID: 27796716
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Evidence That The 5p12 Variant Rs10941679 Confers Susceptibility To Estrogen-receptor-positive Breast Cancer Through Fgf10 And Mrps30 Regulation
Authors: Ghoussaini M. , French J.D. , Michailidou K. , Nord S. , Beesley J. , Canisus S. , Hillman K.M. , Kaufmann S. , Sivakumaran H. , Moradi Marjaneh M. , et al. .
Source: American Journal Of Human Genetics, 2016-10-06 00:00:00.0; 99(4), p. 903-911.
PMID: 27640304
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Patient Survival And Tumor Characteristics Associated With Chek2:p.i157t - Findings From The Breast Cancer Association Consortium
Authors: Muranen T.A. , Blomqvist C. , Dörk T. , Jakubowska A. , Heikkilä P. , Fagerholm R. , Greco D. , Aittomäki K. , Bojesen S.E. , Shah M. , et al. .
Source: Breast Cancer Research : Bcr, 2016-10-03 00:00:00.0; 18(1), p. 98.
PMID: 27716369
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Impact That Timing Of Genetic Mutation Diagnosis Has On Surgical Decision Making And Outcome For Brca1/brca2 Mutation Carriers With Breast Cancer
Authors: Chiba A. , Hoskin T.L. , Hallberg E.J. , Cogswell J.A. , Heins C.N. , Couch F.J. , Boughey J.C. .
Source: Annals Of Surgical Oncology, 2016 Oct; 23(10), p. 3232-8.
PMID: 27338744
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Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers.
Authors: Schmidt M.K. , Hogervorst F. , van Hien R. , Cornelissen S. , Broeks A. , Adank M.A. , Meijers H. , Waisfisz Q. , Hollestelle A. , Schutte M. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2016-08-10 00:00:00.0; 34(23), p. 2750-60.
EPub date: 2016-08-10 00:00:00.0.
PMID: 27269948
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Genetically Predicted Body Mass Index And Breast Cancer Risk: Mendelian Randomization Analyses Of Data From 145,000 Women Of European Descent
Authors: Guo Y. , Warren Andersen S. , Shu X.O. , Michailidou K. , Bolla M.K. , Wang Q. , Garcia-Closas M. , Milne R.L. , Schmidt M.K. , Chang-Claude J. , et al. .
Source: Plos Medicine, 2016 Aug; 13(8), p. e1002105.
PMID: 27551723
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Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.
Authors: Maxwell K.N. , Hart S.N. , Vijai J. , Schrader K.A. , Slavin T.P. , Thomas T. , Wubbenhorst B. , Ravichandran V. , Moore R.M. , Hu C. , et al. .
Source: American Journal Of Human Genetics, 2016-05-05 00:00:00.0; 98(5), p. 801-17.
PMID: 27153395
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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 May; 53(5), p. 298-309.
PMID: 26921362
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Genes associated with histopathologic features of triple negative breast tumors predict molecular subtypes.
Authors: Purrington K.S. , Visscher D.W. , Wang C. , Yannoukakos D. , Hamann U. , Nevanlinna H. , Cox A. , Giles G.G. , Eckel-Passow J.E. , Lakis S. , et al. .
Source: Breast Cancer Research And Treatment, 2016 May; 157(1), p. 117-31.
PMID: 27083182
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.
Authors: Couch F.J. , Kuchenbaecker K.B. , Michailidou K. , Mendoza-Fandino G.A. , Nord S. , Lilyquist J. , Olswold C. , Hallberg E. , Agata S. , Ahsan H. , et al. .
Source: Nature Communications, 2016-04-27 00:00:00.0; 7, p. 11375.
EPub date: 2016-04-27 00:00:00.0.
PMID: 27117709
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Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.
Authors: Dunning A.M. , Michailidou K. , Kuchenbaecker K.B. , Thompson D. , French J.D. , Beesley J. , Healey C.S. , Kar S. , Pooley K.A. , Lopez-Knowles E. , et al. .
Source: Nature Genetics, 2016 Apr; 48(4), p. 374-86.
PMID: 26928228
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Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families.
Authors: Li J. , Meeks H. , Feng B.J. , Healey S. , Thorne H. , Makunin I. , Ellis J. , kConFab Investigators , Campbell I. , Southey M. , et al. .
Source: Journal Of Medical Genetics, 2016 Jan; 53(1), p. 34-42.
PMID: 26534844
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Genomic Biomarkers for Breast Cancer Risk.
Authors: Walsh M.F. , Nathanson K.L. , Couch F.J. , Offit K. .
Source: Advances In Experimental Medicine And Biology, 2016; 882, p. 1-32.
PMID: 26987529
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Gene-panel sequencing and the prediction of breast-cancer risk.
Authors: Easton D.F. , Pharoah P.D. , Antoniou A.C. , Tischkowitz M. , Tavtigian S.V. , Nathanson K.L. , Devilee P. , Meindl A. , Couch F.J. , Southey M. , et al. .
Source: The New England Journal Of Medicine, 2015-06-04 00:00:00.0; 372(23), p. 2243-57.
EPub date: 2015-06-04 00:00:00.0.
PMID: 26014596
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Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls.
Authors: Lilyquist J. , LaDuca H. , Polley E. , Davis B.T. , Shimelis H. , Hu C. , Hart S.N. , Dolinsky J.S. , Couch F.J. , Goldgar D.E. .
Source: Gynecologic Oncology, 2017 11; 147(2), p. 375-380.
EPub date: 2017-09-07 00:00:00.0.
PMID: 28888541
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Cancer susceptibility gene mutations in type I and II endometrial cancer.
Authors: Long B. , Lilyquist J. , Weaver A. , Hu C. , Gnanaolivu R. , Lee K.Y. , Hart S.N. , Polley E.C. , Bakkum-Gamez J.N. , Couch F.J. , et al. .
Source: Gynecologic oncology, 2019 01; 152(1), p. 20-25.
EPub date: 2018-10-26.
PMID: 30612635
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