Charbonneau, Bridget4; Block, Matthew S4; Bamlet, William R4; Vierkant, Robert A4; Kalli, Kimberly R4; Fogarty, Zachary4; Rider, David N4; Sellers, Thomas A4; Tworoger, Shelley S4; Poole, Elizabeth4; Risch, Harvey A4; Salvesen, Helga B4; Kiemeney, Lambertus A4; Baglietto, Laura4; Giles, Graham G4; Severi, Gianluca4; Trabert, Britton4; Wentzensen, Nicolas4; Chenevix-Trench, Georgia4; Whittemore, Alice S4; Sieh, Weiva4; Chang-Claude, Jenny4; Bandera, Elisa V4; Orlow, Irene4; Terry, Kathryn4; Goodman, Marc T4; Thompson, Pamela J4; Cook, Linda S4; Rossing, Mary Anne4; Ness, Roberta B4; Narod, Steven A4; Kupryjanczyk, Jolanta4; Lu, Karen4; Butzow, Ralf4; Dörk, Thilo4; Pejovic, Tanja4; Campbell, Ian4; Le, Nhu D4; Bunker, Clareann H4; Bogdanova, Natalia4; Runnebaum, Ingo B4; Eccles, Diana4; Paul, James4; Wu, Anna H4; Gayther, Simon A4; Hogdall, Estrid4; Heitz, Florian4; Kaye, Stanley B4; Karlan, Beth Y4; Anton-Culver, Hoda4; Gronwald, Jacek4; Hogdall, Claus K5; Lambrechts, Diether4; Fasching, Peter A4; Menon, Usha4; Schildkraut, Joellen4; Pearce, Celeste Leigh4; Levine, Douglas A4; Kjaer, Susanne Kruger5; Cramer, Daniel4; Flanagan, James M4; Phelan, Catherine M4; Brown, Robert4; Massuger, Leon F A G4; Song, Honglin4; Doherty, Jennifer A4; Krakstad, Camilla4; Liang, Dong4; Odunsi, Kunle4; Berchuck, Andrew4; Jensen, Allan6; Lubinski, Jan4; Nevanlinna, Heli4; Bean, Yukie T4; Lurie, Galina4; Ziogas, Argyrios4; Walsh, Christine4; Despierre, Evelyn4; Brinton, Louise4; Hein, Alexander4; Rudolph, Anja4; Dansonka-Mieszkowska, Agnieszka4; Olson, Sara H4; Harter, Philipp4; Tyrer, Jonathan4; Vitonis, Allison F4; Brooks-Wilson, Angela4; Aben, Katja K4; Pike, Malcolm C4; Ramus, Susan J4; Wik, Elisabeth4; Cybulski, Cezary4; Lin, Jie4; Sucheston, Lara4; Edwards, Robert4; McGuire, Valerie4; Lester, Jenny4; du Bois, Andreas4; Lundvall, Lene4; Wang-Gohrke, Shan4; Szafron, Lukasz M4; Lambrechts, Sandrina4; Yang, Hannah4; Beckmann, Matthias W4; Pelttari, Liisa M4; Van Altena, Anne M4; van den Berg, David4; Halle, Mari K4; Gentry-Maharaj, Aleksandra4; Schwaab, Ira4; Chandran, Urmila4; Menkiszak, Janusz4; Ekici, Arif B4; Wilkens, Lynne R4; Leminen, Arto4; Modugno, Francesmary4; Friel, Grace4; Rothstein, Joseph H4; Vergote, Ignace4; Garcia-Closas, Montserrat4; Hildebrandt, Michelle A T4; Sobiczewski, Piotr4; Kelemen, Linda E4; Pharoah, Paul D P4; Moysich, Kirsten4; Knutson, Keith L4; Cunningham, Julie M4; Fridley, Brooke L4; Goode, Ellen L4
1 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet3 Department of Public Health, Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet4 unknown5 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet6 Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet
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. 852-861
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; 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.