Charbonneau, Bridget3; Block, Matthew S3; Bamlet, William R3; Vierkant, Robert A3; Kalli, Kimberly R3; Fogarty, Zachary3; Rider, David N3; Sellers, Thomas A3; Tworoger, Shelley S3; Poole, Elizabeth3; Risch, Harvey A3; Salvesen, Helga B3; Kiemeney, Lambertus A3; Baglietto, Laura3; Giles, Graham G3; Severi, Gianluca3; Trabert, Britton3; Wentzensen, Nicolas3; Chenevix-Trench, Georgia3; Whittemore, Alice S3; Sieh, Weiva3; Chang-Claude, Jenny3; Bandera, Elisa V3; Orlow, Irene3; Terry, Kathryn3; Goodman, Marc T3; Thompson, Pamela J3; Cook, Linda S3; Rossing, Mary Anne3; Ness, Roberta B3; Narod, Steven A3; Kupryjanczyk, Jolanta3; Lu, Karen3; Butzow, Ralf3; Dörk, Thilo3; Pejovic, Tanja3; Campbell, Ian3; Le, Nhu D3; Bunker, Clareann H3; Bogdanova, Natalia3; Runnebaum, Ingo B3; Eccles, Diana3; Paul, James3; Wu, Anna H3; Gayther, Simon A3; Hogdall, Estrid1; Heitz, Florian3; Kaye, Stanley B3; Karlan, Beth Y3; Anton-Culver, Hoda3; Gronwald, Jacek3; Hogdall, Claus K2; Lambrechts, Diether3; Fasching, Peter A3; Menon, Usha3; Schildkraut, Joellen3; Pearce, Celeste Leigh3; Levine, Douglas A3; Kjaer, Susanne Kruger2; Cramer, Daniel3; Flanagan, James M3; Phelan, Catherine M3; Brown, Robert3; Massuger, Leon F A G3; Song, Honglin3; Doherty, Jennifer A3; Krakstad, Camilla3; Liang, Dong3; Odunsi, Kunle3; Berchuck, Andrew3; Jensen, Allan3; Lubinski, Jan3; Nevanlinna, Heli3; Bean, Yukie T3; Lurie, Galina3; Ziogas, Argyrios3; Walsh, Christine3; Despierre, Evelyn3; Brinton, Louise3; Hein, Alexander3; Rudolph, Anja3; Dansonka-Mieszkowska, Agnieszka3; Olson, Sara H3; Harter, Philipp3; Tyrer, Jonathan3; Vitonis, Allison F3; Brooks-Wilson, Angela3; Aben, Katja K3; Pike, Malcolm C3; Ramus, Susan J3; Wik, Elisabeth3; Cybulski, Cezary3; Lin, Jie3; Sucheston, Lara3; Edwards, Robert3; McGuire, Valerie3; Lester, Jenny3; du Bois, Andreas3; Lundvall, Lene2; Wang-Gohrke, Shan3; Szafron, Lukasz M3; Lambrechts, Sandrina3; Yang, Hannah3; Beckmann, Matthias W3; Pelttari, Liisa M3; Van Altena, Anne M3; van den Berg, David3; Halle, Mari K3; Gentry-Maharaj, Aleksandra3; Schwaab, Ira3; Chandran, Urmila3; Menkiszak, Janusz3; Ekici, Arif B3; Wilkens, Lynne R3; Leminen, Arto3; Modugno, Francesmary3; Friel, Grace3; Rothstein, Joseph H3; Vergote, Ignace3; Garcia-Closas, Montserrat3; Hildebrandt, Michelle A T3; Sobiczewski, Piotr3; Kelemen, Linda E3; Pharoah, Paul D P3; Moysich, Kirsten3; Knutson, Keith L3; Cunningham, Julie M3; Fridley, Brooke L3; Goode, Ellen L3
1 Pathology, Herlev and Gentofte Hospital, The Capital Region of Denmark2 Gynækologisk Klinik, Juliane Marie Centre, Rigshospitalet, The Capital Region of Denmark3 unknown
genetic association with IL1A and TNFSF10
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.
Cancer Research, 2014, Vol 74, Issue 3, p. 852-61
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Case-Control Studies; Female; Genetic Association Studies; Humans; Interleukin-1alpha; NF-kappa B; Ovarian Neoplasms; Polymorphism, Single Nucleotide; Risk; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand