Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer
Authors: Block Matthew S. , Charbonneau Bridget , Vierkant Robert A. , Fogarty Zachary , Bamlet William R. , Pharoah Paul D.P. ,   Georgia Chenevix-Trench,   for AOCS,   /ACS Group, Rossing Mary Anne , Cramer Daniel , Pearce Celeste Leigh , Schildkraut Joellen , Menon Usha , Kjaer Susanne K. , Levine Douglas A. , Gronwald Jacek , Culver Hoda Anton , Whittemore Alice S. , Karlan Beth Y. , Lambrechts Diether , Wentzensen Nicolas , Kupryjanczyk Jolanta , Chang-Claude Jenny , Bandera Elisa V. , Hogdall Estrid , Heitz Florian , Kaye Stanley B. , Fasching Peter A. , Campbell Ian , Goodman Marc T. , Pejovic Tanja , Bean Yukie T. , Hays Laura E. , Lurie Galina , Eccles Diana , Hein Alexander , Beckmann Matthias W. , Ekici Arif B. , Paul James , Brown Robert , Flanagan James M. , Harter Philipp , du Bois Andreas , Schwaab Ira , Hogdall Claus K. , Lundvall Lene , Olson Sara H. , Orlow Irene , Paddock Lisa E. , Rudolph Anja , Eilber Ursula , Dansonka-Mieszkowska Agnieszka , Rzepecka Iwona K. , Ziolkowska-Seta Izabela , Brinton Louise A. , Yang Hannah , Garcia-Closas Montserrat , Despierre Evelyn , Lambrechts Sandrina , Vergote Ignace , Walsh Christine S. , Lester Jenny , Sieh Weiva , McGuire Valerie , Rothstein Joseph H. , Ziogas Argyrios , Lubiński Jan , Cybulski Cezary , Menkiszak Janusz , Jensen Allan , Gayther Simon A. , Ramus Susan J. , Gentry-Maharaj Aleksandra , Berchuck Andrew , Wu Anna H. , Pike Malcolm C. , Van Den Berg David , Terry Kathryn L. , Vitonis Allison F. , Ramirez Starr M. , Rider David N. , Knutson Keith L. , Sellers Thomas A. , Phelan Catherine M. , Doherty Jennifer A. , Johnatty Sharon E. , deFazio Anna , Song Honglin , Tyrer Jonathan , Kalli Kimberly R. , Fridley Brooke L. , Cunningham Julie M. , Goode Ellen L. 
Published: April 2014

Abstract
Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P &lt; 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.