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Grant Details

Grant Number: 5R01CA175716-05 Interpret this number
Primary Investigator: King, Mary-Claire
Organization: University Of Washington
Project Title: Complete Variant Profiling of All Known Breast Cancer Genes
Fiscal Year: 2017
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Abstract

DESCRIPTION (provided by applicant): The goal of this project is to identify and characterize clinically actionable mutations in all known breast cancer genes so that they can be incorporated into clinical care. DNA samples from 3000 cases and 2000 ancestry matched controls will be sequenced for all known breast cancer genes. Germline mutations will be evaluated with respect to function and relative risk of breast cancer. The discovery and characterization of clinically actionable variants in breast cancer genes involves three aims. In AIM 1, we will sequence all 18 known breast cancer genes in DNA samples from 3000 women with breast cancer and 2000 ancestry-matched controls. In parallel, we will similarly evaluate 6 new candidate genes for inherited breast cancer that have emerged from our independent family studies. For all characterizations, we will use our recently developed approach for simultaneous capture and multiplexed sequencing, to >300-fold median coverage, of exons, introns, regulatory, and flanking intergenic regions of breast cancer genes. In AIM 2, we will identify all variants predicted to lead to loss of gene function, including truncating mutations (whether nonsense, frameshifts, disrupting CNV and so on), complete genomic deletions, and putatively damaging missense mutations. We will assess all variants for effect on gene function using bioinformatics tools. Variants with possible splice effects will be evaluated by RT-PCR of patient RNA and ex vivo minigenes. The most promising missense alleles will be tested experimentally for DNA damage response, loss of enzyme activity and other functional assays as appropriate. In AIM 3, we will test the strength of association of breast cancer with each of the 24 genes, based on the combined frequency of unambiguous loss-of-function mutations in cases vs controls. Relative risks will be estimated for each gene. The challenge of integrating genomics into clinical care is timely now for inherited predisposition to breast cancer, because multiple causal genes are known, specialized breast screening modalities are available, risk- reducing surgery is effective, and treatment of breast cancer is influenced by the patient's genotype. The goal of this project is to provide the information and technology necessary for this translation.

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Publications

Inherited Breast Cancer in Nigerian Women.
Authors: Zheng Y. , Walsh T. , Gulsuner S. , Casadei S. , Lee M.K. , Ogundiran T.O. , Ademola A. , Falusi A.G. , Adebamowo C.A. , Oluwasola A.O. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2018-10-01 00:00:00.0; 36(28), p. 2820-2825.
EPub date: 2018-08-21 00:00:00.0.
PMID: 30130155
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BARD1 is necessary for ubiquitylation of nucleosomal histone H2A and for transcriptional regulation of estrogen metabolism genes.
Authors: Stewart M.D. , Zelin E. , Dhall A. , Walsh T. , Upadhyay E. , Corn J.E. , Chatterjee C. , King M.C. , Klevit R.E. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2018-02-06 00:00:00.0; 115(6), p. 1316-1321.
EPub date: 2018-01-24 00:00:00.0.
PMID: 29367421
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Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: an NRG Oncology/Gynecologic Oncology Group Study.
Authors: Norquist B.M. , Brady M.F. , Harrell M.I. , Walsh T. , Lee M.K. , Gulsuner S. , Bernards S.S. , Casadei S. , Burger R.A. , Tewari K.S. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2017-11-30 00:00:00.0; , .
EPub date: 2017-11-30 00:00:00.0.
PMID: 29191972
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Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53.
Authors: Lolas Hamameh S. , Renbaum P. , Kamal L. , Dweik D. , Salahat M. , Jaraysa T. , Abu Rayyan A. , Casadei S. , Mandell J.B. , Gulsuner S. , et al. .
Source: International Journal Of Cancer, 2017-08-15 00:00:00.0; 141(4), p. 750-756.
EPub date: 2017-05-19 00:00:00.0.
PMID: 28486781
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Haplotype analyses of the c.1027C>T and c.2167_2168delAT recurrent truncating mutations in the breast cancer-predisposing gene PALB2.
Authors: Catucci I. , Casadei S. , Ding Y.C. , Volorio S. , Ficarazzi F. , Falanga A. , Marchetti M. , Tondini C. , Franchi M. , Adamson A. , et al. .
Source: Breast Cancer Research And Treatment, 2016 Nov; 160(1), p. 121-129.
EPub date: 2016-09-13 00:00:00.0.
PMID: 27624329
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Family-Specific Variants and the Limits of Human Genetics.
Authors: Shirts B.H. , Pritchard C.C. , Walsh T. .
Source: Trends In Molecular Medicine, 2016 Nov; 22(11), p. 925-934.
EPub date: 2016-10-11 00:00:00.0.
PMID: 27742414
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Inherited Dna-repair Gene Mutations In Men With Metastatic Prostate Cancer
Authors: Pritchard C.C. , Mateo J. , Walsh M.F. , De Sarkar N. , Abida W. , Beltran H. , Garofalo A. , Gulati R. , Carreira S. , Eeles R. , et al. .
Source: The New England Journal Of Medicine, 2016-08-04 00:00:00.0; 375(5), p. 443-53.
PMID: 27433846
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Inherited Mutations in Women With Ovarian Carcinoma.
Authors: Norquist B.M. , Harrell M.I. , Brady M.F. , Walsh T. , Lee M.K. , Gulsuner S. , Bernards S.S. , Casadei S. , Yi Q. , Burger R.A. , et al. .
Source: Jama Oncology, 2016 Apr; 2(4), p. 482-90.
PMID: 26720728
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Somatic Mosaic Mutations in PPM1D and TP53 in the Blood of Women With Ovarian Carcinoma.
Authors: Swisher E.M. , Harrell M.I. , Norquist B.M. , Walsh T. , Brady M. , Lee M. , Hershberg R. , Kalli K.R. , Lankes H. , Konnick E.Q. , et al. .
Source: Jama Oncology, 2016 Mar; 2(3), p. 370-2.
PMID: 26847329
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Genetic characterization of early onset ovarian carcinoma.
Authors: Bernards S.S. , Norquist B.M. , Harrell M.I. , Agnew K.J. , Lee M.K. , Walsh T. , Swisher E.M. .
Source: Gynecologic Oncology, 2016 Feb; 140(2), p. 221-5.
EPub date: 2015-12-21 00:00:00.0.
PMID: 26718727
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Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia.
Authors: Churpek J.E. , Marquez R. , Neistadt B. , Claussen K. , Lee M.K. , Churpek M.M. , Huo D. , Weiner H. , Bannerjee M. , Godley L.A. , et al. .
Source: Cancer, 2016-01-15 00:00:00.0; 122(2), p. 304-11.
EPub date: 2015-12-07 00:00:00.0.
PMID: 26641009
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Actionable exomic incidental findings in 6503 participants: challenges of variant classification.
Authors: Amendola L.M. , Dorschner M.O. , Robertson P.D. , Salama J.S. , Hart R. , Shirts B.H. , Murray M.L. , Tokita M.J. , Gallego C.J. , Kim D.S. , et al. .
Source: Genome Research, 2015 Mar; 25(3), p. 305-15.
PMID: 25637381
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Inherited predisposition to breast cancer among African American women.
Authors: Churpek J.E. , Walsh T. , Zheng Y. , Moton Z. , Thornton A.M. , Lee M.K. , Casadei S. , Watts A. , Neistadt B. , Churpek M.M. , et al. .
Source: Breast Cancer Research And Treatment, 2015 Jan; 149(1), p. 31-9.
PMID: 25428789
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Precision medicine meets public health: population screening for BRCA1 and BRCA2.
Authors: Levy-Lahad E. , Lahad A. , King M.C. .
Source: Journal Of The National Cancer Institute, 2015 Jan; 107(1), p. 420.
PMID: 25550384
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Identification of a new BRCA2 large genomic deletion associated with high risk male breast cancer.
Authors: Timoteo A.R. , Albuquerque B.M. , Moura P.C. , Ramos C.C. , Agnez-Lima L.F. , Walsh T. , King M.C. , Lajus T.B. .
Source: Hereditary Cancer In Clinical Practice, 2015; 13(1), p. 2.
EPub date: 2015-01-16 00:00:00.0.
PMID: 25632310
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Deep sequencing with intronic capture enables identification of an APC exon 10 inversion in a patient with polyposis.
Authors: Shirts B.H. , Salipante S.J. , Casadei S. , Ryan S. , Martin J. , Jacobson A. , Vlaskin T. , Koehler K. , Livingston R.J. , King M.C. , et al. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2014 Oct; 16(10), p. 783-6.
PMID: 24675673
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Lasker Award winner Mary-Claire King.
Authors: King M.C. .
Source: Nature Medicine, 2014 Oct; 20(10), p. 1124-5.
PMID: 25295950
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Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2.
Authors: Gabai-Kapara E. , Lahad A. , Kaufman B. , Friedman E. , Segev S. , Renbaum P. , Beeri R. , Gal M. , Grinshpun-Cohen J. , Djemal K. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2014-09-30 00:00:00.0; 111(39), p. 14205-10.
EPub date: 2014-09-30 00:00:00.0.
PMID: 25192939
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Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer.
Authors: Pritchard C.C. , Morrissey C. , Kumar A. , Zhang X. , Smith C. , Coleman I. , Salipante S.J. , Milbank J. , Yu M. , Grady W.M. , et al. .
Source: Nature Communications, 2014-09-25 00:00:00.0; 5, p. 4988.
EPub date: 2014-09-25 00:00:00.0.
PMID: 25255306
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Breast-cancer risk in families with mutations in PALB2.
Authors: Antoniou A.C. , Casadei S. , Heikkinen T. , Barrowdale D. , Pylkäs 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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Germline mutations of inhibins in early-onset ovarian epithelial tumors.
Authors: Tournier I. , Marlin R. , Walton K. , Charbonnier F. , Coutant S. , Théry J.C. , Charbonnier C. , Spurrell C. , Vezain M. , Ippolito L. , et al. .
Source: Human Mutation, 2014 Mar; 35(3), p. 294-7.
PMID: 24302632
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Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
Authors: Pennington K.P. , Walsh T. , Harrell M.I. , Lee M.K. , Pennil C.C. , Rendi M.H. , Thornton A. , Norquist B.M. , Casadei S. , Nord A.S. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2014-02-01 00:00:00.0; 20(3), p. 764-75.
EPub date: 2014-02-01 00:00:00.0.
PMID: 24240112
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Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens.
Authors: Pritchard C.C. , Salipante S.J. , Koehler K. , Smith C. , Scroggins S. , Wood B. , Wu D. , Lee M.K. , Dintzis S. , Adey A. , et al. .
Source: The Journal Of Molecular Diagnostics : Jmd, 2014 Jan; 16(1), p. 56-67.
PMID: 24189654
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Actionable, pathogenic incidental findings in 1,000 participants' exomes.
Authors: Dorschner M.O. , Amendola L.M. , Turner E.H. , Robertson P.D. , Shirts B.H. , Gallego C.J. , Bennett R.L. , Jones K.L. , Tokita M.J. , Bennett J.T. , et al. .
Source: American Journal Of Human Genetics, 2013-10-03 00:00:00.0; 93(4), p. 631-40.
EPub date: 2013-10-03 00:00:00.0.
PMID: 24055113
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Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identified by clinical testing.
Authors: Norquist B.M. , Pennington K.P. , Agnew K.J. , Harrell M.I. , Pennil C.C. , Lee M.K. , Casadei S. , Thornton A.M. , Garcia R.L. , Walsh T. , et al. .
Source: Gynecologic Oncology, 2013 Mar; 128(3), p. 483-7.
PMID: 23262210
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BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma.
Authors: Pennington K.P. , Walsh T. , Lee M. , Pennil C. , Novetsky A.P. , Agnew K.J. , Thornton A. , Garcia R. , Mutch D. , King M.C. , et al. .
Source: Cancer, 2013-01-15 00:00:00.0; 119(2), p. 332-8.
EPub date: 2013-01-15 00:00:00.0.
PMID: 22811390
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Loss of function germline mutations in RAD51D in women with ovarian carcinoma.
Authors: Wickramanayake A. , Wickramanyake A. , Bernier G. , Pennil C. , Casadei S. , Agnew K.J. , Stray S.M. , Mandell J. , Garcia R.L. , Walsh T. , et al. .
Source: Gynecologic Oncology, 2012 Dec; 127(3), p. 552-5.
PMID: 22986143
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ColoSeq provides comprehensive lynch and polyposis syndrome mutational analysis using massively parallel sequencing.
Authors: Pritchard C.C. , Smith C. , Salipante S.J. , Lee M.K. , Thornton A.M. , Nord A.S. , Gulden C. , Kupfer S.S. , Swisher E.M. , Bennett R.L. , et al. .
Source: The Journal Of Molecular Diagnostics : Jmd, 2012 Jul; 14(4), p. 357-66.
PMID: 22658618
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Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.
Authors: Walsh T. , Casadei S. , Lee M.K. , Pennil C.C. , Nord A.S. , Thornton A.M. , Roeb W. , Agnew K.J. , Stray S.M. , Wickramanayake A. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2011-11-01 00:00:00.0; 108(44), p. 18032-7.
EPub date: 2011-11-01 00:00:00.0.
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Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.
Authors: Casadei S. , Norquist B.M. , Walsh T. , Stray S. , Mandell J.B. , Lee M.K. , Stamatoyannopoulos J.A. , King M.C. .
Source: Cancer Research, 2011-03-15 00:00:00.0; 71(6), p. 2222-9.
EPub date: 2011-03-15 00:00:00.0.
PMID: 21285249
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Accurate And Exact Cnv Identification From Targeted High-throughput Sequence Data
Authors: Nord,A.S. , Lee,M. , King,M.C. , Walsh,T. .
Source: Bmc Genomics, 2011; 12, p. 184.
PMID: 21486468
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Detection Of Inherited Mutations For Breast And Ovarian Cancer Using Genomic Capture And Massively Parallel Sequencing
Authors: Walsh,T. , Lee,M.K. , Casadei,S. , Thornton,A.M. , Stray,S.M. , Pennil,C. , Nord,A.S. , Mandell,J.B. , Swisher,E.M. , King,M.C. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2010-07-13 00:00:00.0; 107(28), p. 12629-33.
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Methylation And Protein Expression Of Dna Repair Genes: Association With Chemotherapy Exposure And Survival In Sporadic Ovarian And Peritoneal Carcinomas
Authors: Swisher,E.M. , Gonzalez,R.M. , Taniguchi,T. , Garcia,R.L. , Walsh,T. , Goff,B.A. , Welcsh,P. .
Source: Molecular Cancer, 2009; 8, p. 48.
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Functional And Genomic Approaches Reveal An Ancient Chek2 Allele Associated With Breast Cancer In The Ashkenazi Jewish Population
Authors: Shaag,A. , Walsh,T. , Renbaum,P. , Kirchhoff,T. , Nafa,K. , Shiovitz,S. , Mandell,J.B. , Welcsh,P. , Lee,M.K. , Ellis,N. , et al. .
Source: Human Molecular Genetics, 2005-02-15 00:00:00.0; 14(4), p. 555-63.
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The Founder Mutation Msh2*1906g-->c Is An Important Cause Of Hereditary Nonpolyposis Colorectal Cancer In The Ashkenazi Jewish Population
Authors: Foulkes W.D. , Thiffault I. , Gruber S.B. , Horwitz M. , Hamel N. , Lee C. , Shia J. , Markowitz A. , Figer A. , Friedman E. , et al. .
Source: American Journal Of Human Genetics, 2002 Dec; 71(6), p. 1395-412.
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