Breast cancer is one of the most common cancers in the US with approximately 227,000 new cases of invasive breast cancer and 40,000 breast cancer deaths predicted in 2012. Breast cancer has a strong heritable component with approximately 15% to 20% of cases exhibiting a family history of the disease. Susceptibility to breast cancer is associated with rare germline variants in high-risk genes such as BRCA1 and BRCA2, several intermediate-risk (3 to 5 fold) predisposition genes such as PALB2 and CHEK2, and many common genetic variants associated with modest (<1.5 fold) increased risk of disease. Currently, high-risk genes and intermediate risk genes are used for clinical genetic testing for breast cancer susceptibility and for clinical management of individuals with a family history of breast cancer. However, the known predisposing variants account for less than 50% of all familial breast cancer cases. Thus, many individuals with a family history of breast cancer cannot benefit from informative clinical genetic testing and enhanced cancer risk assessment and management. Although non-genetic factors and additional common genetic variants also may influence breast cancer risk, it is unlikely that these additional factors account for all of te missing heritability of breast cancer. Thus, we hypothesize that a significant amount of the unexplained familial risk of breast cancer is due to rare genetic variants that are associated with intermediate-to-high risk. Herein, we propose to identify and characterize novel breast cancer susceptibility genes using a comprehensive sequence-based approach. We have already completed whole exome sequencing of multiple germline DNA samples from 200 high-risk breast cancer families and now propose to leverage the results from these exome sequencing studies to establish the contribution of candidate variants and genes to breast cancer.
In Aim 1, we will validate 400 candidate genes in a case-control study of 4,000 familial breast cancer cases and 4,000 unaffected controls.
In Aim 2 we will take a different approach to the identification of breast cancer risk factors by evaluating associations between rare recurring protein-coding variants and breast cancer risk. We will use a large case-control study of 8,000 breast cancer cases and 8,000 matched unaffected controls to validate candidates. Finally, in Aim 3 we will conduct functional studies of the candidate genes and variants from Aims 1 and 2 in order to improve prediction of pathogenic and non-pathogenic variants for the validation studies and to understand the signaling mechanisms associated with predisposition to breast cancer. The research team involved in this project has access to large, well annotated patient resources, has an established background in this research, is leveraging extensive preliminary data, and has the ability to utilize the findings for the benefit of breast cancer patients. Thus, his team is well positioned to account for much of the """"""""missing heritability"""""""" of breast cancer.

Public Health Relevance

Common germline variants and mutations in known high and intermediate risk predisposition genes, including BRCA1, BRCA2, PALB2, CHEK2 and BRIP1, do not account for over 50% of familial or young onset breast cancers. This project focuses on leveraging preliminary findings for identification and characterization of additional breast cancer susceptibility genes. The new genes identified in this study will lead to better risk assessment for breast cancer and improved clinical management of breast cancer patients and their family members, perhaps leading to novel or more effective prevention and therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA176785-01A1
Application #
8694379
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Nelson, Stefanie A
Project Start
2014-04-10
Project End
2019-02-28
Budget Start
2014-04-10
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$704,905
Indirect Cost
$143,409
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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(2016) Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nat Genet 48:374-86
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(2016) Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer. Nat Commun 7:11375
(2016) Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types. Cancer Discov 6:1052-67
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Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B et al. (2016) Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium. Hum Genet 135:137-54
Guo, Yan; Warren Andersen, Shaneda; Shu, Xiao-Ou et al. (2016) Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent. PLoS Med 13:e1002105
Easton, Douglas F; Lesueur, Fabienne; Decker, Brennan et al. (2016) No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet 53:298-309

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