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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Konecny, Gottfried E; Wang, Chen; Hamidi, Habib et al. (2014) Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer. J Natl Cancer Inst 106:
Wang, Chen; Cicek, Mine S; Charbonneau, Bridget et al. (2014) Tumor hypomethylation at 6p21.3 associates with longer time to recurrence of high-grade serous epithelial ovarian cancer. Cancer Res 74:3084-91
Larson, Nicholas B; Jenkins, Gregory D; Larson, Melissa C et al. (2014) Kernel canonical correlation analysis for assessing gene-gene interactions and application to ovarian cancer. Eur J Hum Genet 22:126-31
Song, Honglin; Cicek, Mine S; Dicks, Ed et al. (2014) The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet 23:4703-9
Cunningham, J M; Cicek, M S; Larson, N B et al. (2014) Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep 4:4026
Earp, Madalene A; Kelemen, Linda E; Magliocco, Anthony M et al. (2014) Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA. Hum Genet 133:481-97
Fridley, Brooke L; Armasu, Sebastian M; Cicek, Mine S et al. (2014) Methylation of leukocyte DNA and ovarian cancer: relationships with disease status and outcome. BMC Med Genomics 7:21
Trabert, Britton; Ness, Roberta B; Lo-Ciganic, Wei-Hsuan et al. (2014) Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium. J Natl Cancer Inst 106:djt431
Charbonneau, Bridget; Moysich, Kirsten B; Kalli, Kimberly R et al. (2014) Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome. Cancer Immunol Res 2:332-40
Kelemen, Linda E; Terry, Kathryn L; Goodman, Marc T et al. (2014) Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk. Mol Nutr Food Res 58:2023-35

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