Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10
Authors: Charbonneau Bridget , Block Matthew S. , Bamlet William R. , Vierkant Robert A. , Kalli Kimberly R. , Fogarty Zachary , Rider David N. , Sellers Thomas A. , Tworoger Shelley S. , Poole Elizabeth , Risch Harvey A. , Salvesen Helga B. , Kiemeney Lambertus A. , Baglietto Laura , Giles Graham G. , Severi Gianluca , Trabert Britton , Wentzensen Nicolas , Chenevix-Trench Georgia ,   for AOCS/ACS group, Whittemore Alice S. , Sieh Weiva , Chang-Claude Jenny , Bandera Elisa V. , Orlow Irene , Terry Kathryn , Goodman Marc T. , Thompson Pamela J. , Cook Linda S. , Rossing Mary Anne , Ness Roberta B. , Narod Steven A. , Kupryjanczyk Jolanta , Lu Karen , Butzow Ralf , Dörk Thilo , Pejovic Tanja , Campbell Ian , Le Nhu D. , Bunker Clareann H. , Bogdanova Natalia , Runnebaum Ingo B. , Eccles Diana , Paul James , Wu Anna H. , Gayther Simon A. , Hogdall Estrid , Heitz Florian , Kaye Stanley B. , Karlan Beth Y. , Anton-Culver Hoda , Gronwald Jacek , Hogdall Claus K. , Lambrechts Diether , Fasching Peter A. , Menon Usha , Schildkraut Joellen , Pearce Celeste Leigh , Levine Douglas A. , Kjaer Susanne Kruger , Cramer Daniel , Flanagan James M. , Phelan Catherine M. , Brown Robert , Massuger Leon F.A.G. , Song Honglin , Doherty Jennifer A. , Krakstad Camilla , Liang Dong , Odunsi Kunle , Berchuck Andrew , Jensen Allan , Lubiński Jan , Nevanlinna Heli , Bean Yukie T. , Lurie Galina , Ziogas Argyrios , Walsh Christine , Despierre Evelyn , Brinton Louise , Hein Alexander , Rudolph Anja , Dansonka-Mieszkowska Agnieszka , Olson Sara H. , Harter Philipp , Tyrer Jonathan , Vitonis Allison F. , Brooks-Wilson Angela , Aben Katja K. , Pike Malcolm C. , Ramus Susan J. , Wik Elisabeth , Cybulski Cezary , Lin Jie , Sucheston Lara , Edwards Robert , McGuire Valerie , Lester Jenny , du Bois Andreas , Lundvall Lene , Wang-Gohrke Shan , Szafron Lukasz M. , Lambrechts Sandrina , Yang Hannah , Beckmann Matthias W. , Pelttari Liisa M. , Van Altena Anne M. , van den Berg David , Halle Mari K. , Gentry-Maharaj Aleksandra , Schwaab Ira , Chandran Urmila , Menkiszak Janusz , Ekici Arif B. , Wilkens Lynne R. , Leminen Arto , Modugno Francesmary , Friel Grace , Rothstein Joseph H. , Vergote Ignace , Garcia-Closas Montserrat , Hildebrandt Michelle A.T. , Sobiczewski Piotr , Kelemen Linda E. , Pharoah Paul D.P. , Moysich Kirsten , Knutson Keith L. , Cunningham Julie M. , Fridley Brooke L. , Goode Ellen L. 
Published: November 2013

Abstract
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 &lt; 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. Cancer Res; 74(3); 852–61. ©2013 AACR.