Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10

Bridget Charbonneau, Matthew S. Block, William R. Bamlet, Robert A. Vierkant, Kimberly R. Kalli, Zachary Fogarty, David N. Rider, Thomas A. Sellers, Shelley S. Tworoger, Elizabeth Poole, Harvey A. Risch, Helga B. Salvesen, Lambertus A. Kiemeney, Laura Baglietto, Graham G. Giles, Gianluca Severi, Britton Trabert, Nicolas Wentzensen, Georgia Chenevix-Trench, for AOCS/ACS group, Alice S. Whittemore, Weiva Sieh, Jenny Chang-Claude, Elisa V. Bandera, Irene Orlow, Kathryn Terry, Marc T. Goodman, Pamela J. Thompson, Linda S. Cook, Mary Anne Rossing, Roberta B. Ness, Steven A. Narod, Jolanta Kupryjanczyk, Karen Lu, Ralf Butzow, Thilo Dörk, Tanja Pejovic, Ian Campbell, Nhu D. Le, Clareann H. Bunker, Natalia Bogdanova, Ingo B. Runnebaum, Diana Eccles, James Paul, Anna H. Wu, Simon A. Gayther, Estrid Hogdall, Florian Heitz, Stanley B. Kaye, Beth Y. Karlan, Hoda Anton-Culver, Jacek Gronwald, Claus K. Hogdall, Diether Lambrechts, Peter A. Fasching, Usha Menon, Joellen Schildkraut, Celeste Leigh Pearce, Douglas A. Levine, Susanne Kruger Kjaer, Daniel Cramer, James M. Flanagan, Catherine M. Phelan, Robert Brown, Leon F.A.G. Massuger, Honglin Song, Jennifer A. Doherty, Camilla Krakstad, Dong Liang, Kunle Odunsi, Andrew Berchuck, Allan Jensen, Jan Lubiński, Heli Nevanlinna, Yukie T. Bean, Galina Lurie, Argyrios Ziogas, Christine Walsh, Evelyn Despierre, Louise Brinton, Alexander Hein, Anja Rudolph, Agnieszka Dansonka-Mieszkowska, Sara H. Olson, Philipp Harter, Jonathan Tyrer, Allison F. Vitonis, Angela Brooks-Wilson, Katja K. Aben, Malcolm C. Pike, Susan J. Ramus, Elisabeth Wik, Cezary Cybulski, Jie Lin, Lara Sucheston, Robert Edwards, Valerie McGuire, Jenny Lester, Andreas du Bois, Lene Lundvall, Shan Wang-Gohrke, Lukasz M. Szafron, Sandrina Lambrechts, Hannah Yang, Matthias W. Beckmann, Liisa M. Pelttari, Anne M. Van Altena, David van den Berg, Mari K. Halle, Aleksandra Gentry-Maharaj, Ira Schwaab, Urmila Chandran, Janusz Menkiszak, Arif B. Ekici, Lynne R. Wilkens, Arto Leminen, Francesmary Modugno, Grace Friel, Joseph H. Rothstein, Ignace Vergote, Montserrat Garcia-Closas, Michelle A.T. Hildebrandt, Piotr Sobiczewski, Linda E. Kelemen, Paul D.P. Pharoah, Kirsten Moysich, Keith L. Knutson, Julie M. Cunningham, Brooke L. Fridley, Ellen L. Goode

A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.