Grant Number:	1R01CA157744-01 Interpret this number
Primary Investigator:	King, Mary-Claire
Organization:	University Of Washington
Project Title:	Discovery of New Genes for Inherited Predisposition to Breast Cancer By Exome Seq
Fiscal Year:	2011

DESCRIPTION (provided by applicant): The goal of this project is to identify new genes for inherited susceptibility to breast cancer. DNA capture and massively parallel sequencing technologies will be exploited to identify these genes in a cohort of 1822 families, each with at least four relatives with breast cancer. The genetic causes of breast cancer in more than 1500 of these families remain unresolved. Discovery of new breast cancer genes in these families involves three aims. In AIM 1, all known genes for inherited predisposition to breast cancer will be fully sequenced in all affected relatives from 150 of the families. The probands of all unresolved families have wildtype sequences at BRCA1, BRCA2, CHEK2, PALB2, CHEK2, BRIP1, p53, and PTEN. However, other affected family members may carry mutations in these genes, and the proband may be a sporadic case. Constitutional DNA of affected relatives will be used to prepare paired-end libraries, which will be hybridized to custom oligonucleotide pools to capture all known breast cancer susceptibility genes, then the enriched libraries will be bar-coded and sequenced in a multiplex design on an Illumina GAIIx genome analyzer. Mutations will be validated by Sanger sequencing. In AIM 2, the Illumina platform will be used again, to fully sequence the entire exomes of all women in the screen with wildtype sequences at all known breast cancer genes. Variants will be filtered to identify rare nonsense mutations, frameshifts, splice site mutations, and genomic deletions and duplications that disrupt genes. Filtered mutations will be validated and tested for co-inheritance with breast cancer. Multiple deleterious mutations are a hallmark of all known genes for inherited breast cancer and are the strongest proof of functional consequence of new breast cancer genes. In Aim 3A, the most promising candidate genes will be fully sequenced in DNA samples from an independent series of familial breast cancer patients to reveal additional mutations. In Aim 3B, potentially functional mutations in these genes will be genotyped by TaqMan assays in large follow-up series to estimate individual and gene-wide mutation frequencies and relative risks. Discovery of new breast cancer susceptibility genes will allow prevention strategies to be extended to families for which causal genes are currently unknown, to better identify women at risk, to allow closer medical surveillance of these women, to stimulate design of new prevention strategies based on genetic evidence, and to offer a better understanding of the biological pathways involved in breast cancer development. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify new genes for inherited susceptibility to breast cancer using DNA capture and next generation sequencing technologies. Discovery of new breast cancer susceptibility genes will allow prevention strategies to be extended to families for which causal genes are currently unknown.




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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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.
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MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform.
Authors: Grati M. , Yan D. , Raval M.H. , Walsh T. , Ma Q. , Chakchouk I. , Kannan-Sundhari A. , Mittal R. , Masmoudi S. , Blanton S.H. , et al. .
Source: Human Mutation, 2016 May; 37(5), p. 481-7.
EPub date: 2016-02-16 00:00:00.0.
PMID: 26841241
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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.
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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.
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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.
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Authors: Morino H. , Pierce S.B. , Matsuda Y. , Walsh T. , Ohsawa R. , Newby M. , Hiraki-Kamon K. , Kuramochi M. , Lee M.K. , Klevit R.E. , et al. .
Source: Neurology, 2014-11-25 00:00:00.0; 83(22), p. 2054-61.
EPub date: 2014-10-29 00:00:00.0.
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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.
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Authors: King M.C. .
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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.
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Authors: King M.C. , Levy-Lahad E. , Lahad A. .
Source: Jama, 2014-09-17 00:00:00.0; 312(11), p. 1091-2.
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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.
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"The race" to clone BRCA1.
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Authors: Tournier I. , Marlin R. , Walton K. , Charbonnier F. , Coutant S. , Théry J.C. , Charbonnier C. , Spurrell C. , Vezain M. , Ippolito L. , et al. .
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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.
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Source: The Journal Of Molecular Diagnostics : Jmd, 2014 Jan; 16(1), p. 56-67.
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Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2013 Dec; 15(12), p. 1004-7.
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Source: American Journal Of Human Genetics, 2013-10-03 00:00:00.0; 93(4), p. 697-710.
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