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.

Public Health Relevance

The goal of this project is to characterize all known breast cancer genes to identify clinically actionable mutations so that they can be incorporated into clinical care. DNA samples from 3000 cases and 2000 ancestry matched controls will be sequenced for 24 known breast cancer genes. Mutations will be evaluated with respect to function and relative risk of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA175716-02
Application #
8744265
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Filipski, Kelly
Project Start
2013-09-30
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Norquist, Barbara M; Harrell, Maria I; Brady, Mark F et al. (2016) Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2:482-90
Levy-Lahad, Ephrat; Lahad, Amnon; King, Mary-Claire (2015) Precision medicine meets public health: population screening for BRCA1 and BRCA2. J Natl Cancer Inst 107:420
Churpek, Jane E; Walsh, Tom; Zheng, Yonglan et al. (2015) Inherited predisposition to breast cancer among African American women. Breast Cancer Res Treat 149:31-9
Antoniou, Antonis C; Casadei, Silvia; Heikkinen, Tuomas et al. (2014) Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506
Gabai-Kapara, Efrat; Lahad, Amnon; Kaufman, Bella et al. (2014) Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A 111:14205-10
Shirts, Brian H; Salipante, Stephen J; Casadei, Silvia et al. (2014) Deep sequencing with intronic capture enables identification of an APC exon 10 inversion in a patient with polyposis. Genet Med 16:783-6
King, Mary-Claire (2014) Lasker Award winner Mary-Claire King. Nat Med 20:1124-5
Norquist, Barbara M; Pennington, Kathryn P; Agnew, Kathy J et al. (2013) Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identified by clinical testing. Gynecol Oncol 128:483-7
Pennington, Kathryn P; Walsh, Tom; Lee, Ming et al. (2013) BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer 119:332-8
Casadei, Silvia; Norquist, Barbara M; Walsh, Tom et al. (2011) Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res 71:2222-9