Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, S. S., Poole, E., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A. S., Sieh, W., Chang-Claude, J., Bandera, E. V., Orlow, I., Terry, K., Goodman, M. T., Thompson, P. J., Cook, L. S., Rossing, M. A., Ness, R. B., Narod, S. A., Kupryjanczyk, J., Lu, K. R., Butzow, R., Dork, T., Pejovic, T., Campbell, I., Le, N. D., Bunker, C. H., Bogdanova, N., Runnebaum, I. B., Eccles, D., Paul, J., Wu, A. N. H., Gayther, S. A., Hogdall, E., Heitz, F., Kaye, S. B., Karlan, B. Y., Anton-Culver, H., Gronwald, J., Hogdall, C. K., Lambrechts, D., Fasching, P. A., Menon, U., Schildkraut, J., Pearce, C. L., Levine, D. A., Kjaer, S. K., Cramer, D., Flanagan, J. M., Phelan, C. M., Brown, R., Massuger, Lfag, Song, H. L., Doherty, J. A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y. T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S. H., Harter, P., Tyrer, J., Vitonis, A. F., Brooks-Wilson, A., Aben, K. K., Pike, M. C., Ramus, S. J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, R., McGuire, V., Lester, J., du Bois, A., Lundvall, L., Wang-Gohrke, S., et al. (2014) Risk of Ovarian Cancer and the NF-kappa B Pathway: Genetic Association with IL1A and TNFSF10. CANCER RESEARCH, 74 (3). pp. 852-861. ISSN 0008-5472

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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-1 alpha (IL1A) is both regulated by and able to activate NF-kappa B, 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-kB 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 x 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.

Item Type:	Article
Authors (ICR Faculty only):	Kaye, Stan and Garcia-Closas, Montse
All Authors:	Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, S. S., Poole, E., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A. S., Sieh, W., Chang-Claude, J., Bandera, E. V., Orlow, I., Terry, K., Goodman, M. T., Thompson, P. J., Cook, L. S., Rossing, M. A., Ness, R. B., Narod, S. A., Kupryjanczyk, J., Lu, K. R., Butzow, R., Dork, T., Pejovic, T., Campbell, I., Le, N. D., Bunker, C. H., Bogdanova, N., Runnebaum, I. B., Eccles, D., Paul, J., Wu, A. N. H., Gayther, S. A., Hogdall, E., Heitz, F., Kaye, S. B., Karlan, B. Y., Anton-Culver, H., Gronwald, J., Hogdall, C. K., Lambrechts, D., Fasching, P. A., Menon, U., Schildkraut, J., Pearce, C. L., Levine, D. A., Kjaer, S. K., Cramer, D., Flanagan, J. M., Phelan, C. M., Brown, R., Massuger, Lfag, Song, H. L., Doherty, J. A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y. T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S. H., Harter, P., Tyrer, J., Vitonis, A. F., Brooks-Wilson, A., Aben, K. K., Pike, M. C., Ramus, S. J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, R., McGuire, V., Lester, J., du Bois, A., Lundvall, L., Wang-Gohrke, S., et al.
Additional Information:	ISI Document Delivery No.: AA4NX Times Cited: 0 Cited Reference Count: 58 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 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 Doerk, 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 Lubinski, 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. European Community [223175, HEALTH-F2-2009-223175; COGS]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692, C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689]; NIH [CA128978]; Post-Cancer GWAS initiative [1 U19 CA 148537]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; Kathryn Sladek Smith [PPD/RPCI.07]; US National Cancer Institute GAME-ON Post-GWAS Initiative [U19-CA148112]; Wellcome Trust [076113]; Deutsche Krebshilfe; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; Canadian Institutes of Health Research New Investigator award [MSH-87734]; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; American Cancer Society [CRTG-00-196-01-CCE]; California Cancer Research Program [00-01389V-20170, N01-CN25403, 2II0200]; Canadian Institutes for Health Research [MOP-86727]; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Celma Mastry Ovarian Cancer Foundation the Danish Cancer Society [94-222-52]; ELAN Funds of the University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Sigrid Juselius Foundation; Imperial Experimental Cancer Research Centre [C1312/A15589]; Nationaal Kankerplan of Belgium; L & S Milken Foundation; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Roswell Park Cancer Institute Alliance Foundation; U.S. Army Medical Research and Materiel Command [W81XWH-07-1-0449]; U.S. National Cancer Institute [K07-CA80668, K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966]; Intramural research funds; NIH/National Center for Research Resources/General Clinical Research Center [MO1-RR000056]; U.S. Army Medical Research and Material Command [DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669]; National Health and Medical Research Council of Australia [199600, 400281, 209057, 251533, 396414, 504715]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; state of Baden-Wurttembergthrough Medical Faculty of the University of Ulm [P.685]; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College London Hospital; Royal Marsden Hospital; WorkSafeBC; Helse Vest; Norwegian Cancer Society; Research Council of Norway (HBS/NOR); [R25 CA92049] Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692), the NIH (CA128978) and Post-Cancer GWAS initiative (No. 1 U19 CA 148537-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.The OCAC is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of the data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available at http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113.B. Charbonneau is supported by R25 CA92049. G. Chenevix-Trench and P.A. Fasching are supported by the Deutsche Krebshilfe. B.Y. Karlan holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). L.E. Kelemen is supported by a Canadian Institutes of Health Research New Investigator award (MSH-87734).Funding of the constituent studies was provided by the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research (MOP-86727); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation the Danish Cancer Society (94-222-52); ELAN Funds of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Sigrid Juselius Foundation; Imperial Experimental Cancer Research Centre (C1312/A15589); the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the U.S. Army Medical Research and Materiel Command (W81XWH-07-1-0449); the U.S. National Cancer Institute (K07-CA80668, K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, and Intramural research funds); NIH/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056; the U.S. Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669); the National Health and Medical Research Council of Australia (199600, 400281, 209057, 251533, 396414, 504715); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-Wurttembergthrough Medical Faculty of the University of Ulm (P.685); the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College London Hospital and the Royal Marsden Hospital; WorkSafeBC; Helse Vest, The Norwegian Cancer Society, The Research Council of Norway (HBS/NOR). Amer assoc cancer research Philadelphia
Uncontrolled Keywords:	nonsteroidal antiinflammatory drugs single-nucleotide polymorphisms pelvic-inflammatory-disease genome-wide association oral-contraceptives reproductive factors epithelial-cells activation population apoptosis
Research teams:	ICR divisions > Cancer Therapeutics > Medicine (Kaye Drug Development Unit) ICR divisions > Clinical Studies > Medicine (Kaye Drug Development Unit) Closed research groups > Molecular Epidemiology
Depositing User:	Alexander Smithson
Date Deposited:	20 Mar 2014 10:23
Last Modified:	09 Dec 2015 13:07
URI:	http://publications.icr.ac.uk/id/eprint/13111

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