We will conduct a comprehensive molecular epidemiologic investigation of the role that genetic variation in the NF-kappaB pathway plays in ovarian cancer etiology. Substantial evidence suggests that inflammation, apoptosis, and immune response processes are linked to ovarian carcinogenesis. NF-kappaB is a family of transcription factors central to these processes which regulates the expression of numerous genes. We hypothesize that genetic variation in NF-kappaB subunits or NF-kappaB inhibitors and activators may modify the activity of NF-kappaB and lead to inter-individual differences in inflammation, apoptosis, and immune response. We will use a three-phase study design to examine whether this genetic variation (specifically, over 3,000 informative polymorphisms in 260 NF-kappaB-related genes) is associated with risk of ovarian cancer. The first two phases of this work will consist of a split-sample group sequential analysis of participants recruited in ongoing ovarian cancer studies at the Mayo Clinic in Rochester, MN and at Duke University in Durham, NC including 1,700 cases and 1,800 frequency-matched controls. The third phase of our study consists of external validation of approximately 50 polymorphisms using data from ongoing studies at the Queensland Institute of Medical Research, Australia, and the University of Cambridge, UK. This comprehensive pathway-based, multiple-phase, linkage disequilibrium-focused approach incorporates design elements at the forefront of epidemiologic methodology. In total, this study will provide excellent statistical power to detect moderately-increased odds ratios. Our goal is to identify the subset of genes which are most relevant to ovarian cancer from among 260 candidate genes encoding NF-kappaB subunits and regulatory molecules. The """"""""shortlist"""""""" of genes and genetic variants showing replicated associations throughout each phase of the study will then be transitioned into downstream functional analysis by our transdisciplinary team for the identification of future preventive and therapeutic strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Epidemiology of Cancer Study Section (EPIC)
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Seminara, Daniela
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Mayo Clinic, Rochester
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Larson, Nicholas B; Fogarty, Zachary C; Larson, Melissa C et al. (2017) An integrative approach to assess X-chromosome inactivation using allele-specific expression with applications to epithelial ovarian cancer. Genet Epidemiol 41:898-914
Praestegaard, Camilla; Jensen, Allan; Jensen, Signe M et al. (2017) Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies. Int J Cancer 140:2422-2435
Glubb, Dylan M; Johnatty, Sharon E; Quinn, Michael C J et al. (2017) Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci. Oncotarget 8:64670-64684
Amos, Christopher I; Dennis, Joe; Wang, Zhaoming et al. (2017) The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers. Cancer Epidemiol Biomarkers Prev 26:126-135
Babic, Ana; Cramer, Daniel W; Kelemen, Linda E et al. (2017) Predictors of pretreatment CA125 at ovarian cancer diagnosis: a pooled analysis in the Ovarian Cancer Association Consortium. Cancer Causes Control 28:459-468
Wang, Chen; Armasu, Sebastian M; Kalli, Kimberly R et al. (2017) Pooled Clustering of High-Grade Serous Ovarian Cancer Gene Expression Leads to Novel Consensus Subtypes Associated with Survival and Surgical Outcomes. Clin Cancer Res 23:4077-4085
Ovarian Tumor Tissue Analysis (OTTA) Consortium (2017) Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer. JAMA Oncol 3:e173290
Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan et al. (2017) Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci. Br J Cancer 116:524-535
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
Dicks, Ed; Song, Honglin; Ramus, Susan J et al. (2017) Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene. Oncotarget 8:50930-50940

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