Inheritance of a germline mutation in the BRCA1 or BRCA2 (BRCA1/2) genes is associated with an increased risk of developing breast and ovarian cancer. However, there is also substantial variability in the penetrance of breast cancer in BRCA1/2 mutation carriers. These observations imply that germline mutations in BRCA1/2 may be necessary to explain the Mendelian pattern of cancer in some families, but may not be sufficient to completely describe the inter-individual variability in the age-specific risk of cancer. There is substantial evidence that BRCA1/2-associated breast carcinogenesis involves the recognition and repair of DNA damage to maintain genomic integrity. The goal of this proposal is to identify genotypes involved in DNA damage recognition and repair pathways that influence BRCA 1/2-associated breast cancer risk. This proposal will be facilitated by the resources of a multidisciplinary collaborative group that has collected data on over 2,000 BRCA1/2 mutation carriers. This existing data resource provides a unique opportunity to accomplish the following specific aims. We hypothesize that in the presence of a mutated BRCA1 or BRCA2 gene, additional inherited variants that confer additional impairment to DNA damage recognition or repair will alter the penetrance of breast cancer. The goal of this proposal is to identify genotypes involved in DNA damage recognition and repair pathways that influence BRCA1/2-associated cancer risk. This proposal will be facilitated by the resources of a multidisciplinary collaborative group that has collected data on over 2,000 BRCA1/2 mutation carriers. We propose to increase the size of this cohort during the funding period and generate and epidemiologically appropriate nested study sample to accomplish the following specific aims:
Specific Aim 1 : To use a case-only study of BRCA1/2 mutation carriers to evaluate whether candidate genes alter the characteristics of breast tumors;
Specific Aim 2 : To use a nested case-control study to evaluate whether candidate genes are associated with altered breast cancer risk;
Specific Aim 3 : To use a nested case-control study to evaluate whether candidate genes predict cancer site (breast vs. ovarian). Knowledge about cancer risk modifiers may improve our risk assessment ability, identify relevant pathways of BRCA1/2-mediated carcinogenesis, and identify exposures that can be used to develop appropriate cancer prevention strategies. Our substantial multidisciplinary experience will therefore allow us to readily translate basic science and epidemiological data to clinically relevant information.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102776-03
Application #
7092131
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Seminara, Daniela
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2006-07-31
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$610,463
Indirect Cost
Name
University of Pennsylvania
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Rebbeck, Timothy R (see original citation for additional authors) (2018) Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat 39:593-620
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
Hamdi, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B et al. (2017) Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3. Breast Cancer Res Treat 161:117-134
Rebbeck, Timothy R; Friebel, Tara M; Mitra, Nandita et al. (2016) Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. Breast Cancer Res 18:112
Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2 (see original citation for additional authors) (2016) No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer. Gynecol Oncol 141:386-401
Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie et al. (2016) Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2. Breast Cancer Res 18:15
Lawrenson, Kate (see original citation for additional authors) (2016) Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nat Commun 7:12675
Shu, Catherine A; Pike, Malcolm C; Jotwani, Anjali R et al. (2016) Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations. JAMA Oncol 2:1434-1440
Zeng, Chenjie (see original citation for additional authors) (2016) Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. Breast Cancer Res 18:64
Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel et al. (2015) Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers. PLoS One 10:e0120020

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