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.
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.
|Barrdahl, Myrto; Rudolph, Anja; Hopper, John L et al. (2017) Gene-environment interactions involving functional variants: Results from the Breast Cancer Association Consortium. Int J Cancer 141:1830-1840|
|Walker, Logan C; Marquart, Louise; Pearson, John F et al. (2017) Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers. Eur J Hum Genet 25:432-438|
|Kuchenbaecker, Karoline B; McGuffog, Lesley; Barrowdale, Daniel et al. (2017) Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers. J Natl Cancer Inst 109:|
|Michailidou, Kyriaki (see original citation for additional authors) (2017) Association analysis identifies 65 new breast cancer risk loci. Nature 551:92-94|
|Brouckaert, Olivier; Rudolph, Anja; Laenen, Annouschka et al. (2017) Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study. Breast Cancer Res 19:119|
|Fagerholm, Rainer; Khan, Sofia; Schmidt, Marjanka K et al. (2017) TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer. Oncotarget 8:18381-18398|
|Phelan, Catherine M (see original citation for additional authors) (2017) Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat Genet 49:680-691|
|Milne, Roger L (see original citation for additional authors) (2017) Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet 49:1767-1778|
|Shimelis, Hermela; Mesman, Romy L S; Von Nicolai, Catharina et al. (2017) BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer. Cancer Res 77:2789-2799|
|Muranen, Taru A; Greco, Dario; Blomqvist, Carl et al. (2017) Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. Genet Med 19:599-603|
Showing the most recent 10 out of 57 publications