Background: Individuals with germline mutations in the BRCA1 tumor suppressor gene account for approximately 10% of ovarian cancer cases. BRCA1 mutation carriers have a substantially increased risk of developing breast and ovarian cancers as compared to the general population. The cumulative risk of ovarian cancer by age 70 for BRCA1 mutation carriers is estimated at 39%, whereas the cumulative risk in the general population is about 1%. However, there is substantial inter-individual variability in the age at diagnosis and the site of cancer occurrence (breast and/or ovarian cancer) in BRCA1 mutation carriers. These observations suggest the existence of genetic and environmental factors that modify the age-specific risk of ovarian cancer for BRCA1 mutation carriers. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), has recently confirmed the existence of genetic modifiers of cancer risk in BRCA1 mutation carriers, through the identification of several single nucleotide polymorphisms (SNPs) that substantially modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. CIMBA has also shown that these SNPs can be used to identify women at higher and lower risk of cancer than the average BRCA1 or BRCA2 mutation carrier, suggesting that risk modifiers in the BRCA1 and BRCA2 populations may add substantially to current risk assessment methods. These efforts to identify risk modifiers for breast cancer are currently being extended in the form of a genome wide association study involving 11,000 BRCA1 mutation carriers. Objective/Hypothesis: Based on these findings, we hypothesize that common genetic variants that modify ovarian cancer risk in BRCA1 mutation carriers also exist. Here we propose to extend the BRCA1 breast cancer GWAS to a BRCA1 ovarian cancer GWAS with the intent of identify SNPs that influence ovarian cancer risk. Overall, our goal is to identify previously undefined genetic risk factors involved in the modification of ovarian cancer risk in BRCA1 carriers with the intent of developing risk models to identify BRCA1 carriers at increased and decreased risk of ovarian cancer. Specific Aims: To identify genetic modifiers of ovarian cancer risk in BRCA1 carriers we propose to conduct a two-stage GWAS using DNA samples from BRCA1 mutation carriers collected through CIMBA. The specific aims are (1) To conduct a genome-wide association scan in 1,000 BRCA1 carriers with ovarian cancer and 1,000 unaffected BRCA1 carriers. (2) To further evaluate observed associations between ovarian cancer risk and SNPs implicated in Aim 1 by genotyping 1,500 additional BRCA1 ovarian cancer cases and 1,500 unaffected BRCA1 carriers. (3) To evaluate risk modifiers from the BRCA1 breast cancer GWAS and risk factors from sporadic ovarian cancer GWAS as modifiers of ovarian cancer in BRCA1 carriers. Study Design: A total of 572 DNA samples from BRCA1 carriers with ovarian cancer and 978 unaffected BRCA1 carriers have been genotyped through the BRCA1 breast cancer GWAS. Here we will genotype an additional 408 BRCA1 carriers with ovarian cancer on Human660W-Quad arrays, add the genotypes to the available data, and analyze the genotype data from the 1,000 affected and 978 unaffected carriers to rank SNPs by significance of association with ovarian cancer risk. Adjustments for study site, population stratification, relatedness, and survival bias will be incorporated. In Aim 2, the 384 SNPs most significantly associated with ovarian cancer will be genotyped on another 1,500 BRCA1 carriers with ovarian cancer and 1,500 unaffecteds. The genotype data from Aims 1 and 2 will be combined and the SNPs associated with ovarian cancer with genome-wide levels of significance will be identified as risk modifiers for ovarian cancer in BRCA1 mutation carriers. In Aim 3, the top hits from the BRCA1 breast and two sporadic ovarian GWAS will also be tested for associations with ovarian cancer in BRCA1 carriers. The influence of the identified SNPs on the cumulative risk of ovarian cancer in the BRCA1 population will then be estimated. Impact: Proper assessment of ovarian cancer risk in BRCA1 mutation carriers is of clinical significance because no effective screening strategies for the early detection of ovarian cancer exist, and most ovarian tumors are diagnosed at a late stage with poor prognosis. Thus, women are counseled to consider risk-reducing salpingooophorectomy (RRSO), preferably prior to age 40. Although RRSO significantly reduces ovarian and breast cancer risk, and may impact mortality, the induction of surgical menopause is associated with menopausal symptoms, which can significantly affect quality of life, and also may lead to osteoporosis and premature cardiac disease. The SNPs identified in this unique study may aid in the identification of women at lower or, alternatively, very-high risk of ovarian cancer and may lead to changes in the clinical care of these women. The SNPs may also prove useful as biomarkers of susceptibility.
|Effective start/end date||5/15/10 → 6/14/14|
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