Charbonneau, Bridget2; Moysich, Kirsten B2; Kalli, Kimberly R2; Oberg, Ann L2; Vierkant, Robert A2; Fogarty, Zachary C2; Block, Matthew S2; Maurer, Matthew J2; Goergen, Krista M2; Fridley, Brooke L2; Cunningham, Julie M2; Rider, David N2; Preston, Claudia2; Hartmann, Lynn C2; Lawrenson, Kate2; Wang, Chen2; Tyrer, Jonathan2; Song, Honglin2; deFazio, Anna2; Johnatty, Sharon E2; Doherty, Jennifer A2; Phelan, Catherine M2; Sellers, Thomas A2; Ramirez, Starr M2; Vitonis, Allison F2; Terry, Kathryn L2; Van Den Berg, David2; Pike, Malcolm C2; Wu, Anna H2; Berchuck, Andrew2; Gentry-Maharaj, Aleksandra2; Ramus, Susan J2; Diergaarde, Brenda2; Shen, Howard2; Jensen, Allan2; Menkiszak, Janusz2; Cybulski, Cezary2; Lubiłski, Jan2; Ziogas, Argyrios2; Rothstein, Joseph H2; McGuire, Valerie2; Sieh, Weiva2; Lester, Jenny2; Walsh, Christine2; Vergote, Ignace2; Lambrechts, Sandrina2; Despierre, Evelyn2; Garcia-Closas, Montserrat2; Yang, Hannah2; Brinton, Louise A2; Spiewankiewicz, Beata2; Rzepecka, Iwona K2; Dansonka-Mieszkowska, Agnieszka2; Seibold, Petra2; Rudolph, Anja2; Paddock, Lisa E2; Orlow, Irene2; Lundvall, Lene2; Olson, Sara H2; Hogdall, Claus K3; Schwaab, Ira2; du Bois, Andreas2; Harter, Philipp2; Flanagan, James M2; Brown, Robert2; Paul, James2; Ekici, Arif B2; Beckmann, Matthias W2; Hein, Alexander2; Eccles, Diana2; Lurie, Galina2; Hays, Laura E2; Bean, Yukie T2; Pejovic, Tanja2; Goodman, Marc T2; Campbell, Ian2; Fasching, Peter A2; Konecny, Gottfried2; Kaye, Stanley B2; Heitz, Florian2; Hogdall, Estrid2; Bandera, Elisa V2; Chang-Claude, Jenny2; Kupryjanczyk, Jolanta2; Wentzensen, Nicolas2; Lambrechts, Diether2; Karlan, Beth Y2; Whittemore, Alice S2; Culver, Hoda Anton2; Gronwald, Jacek2; Levine, Douglas A2; Kjaer, Susanne K3; Menon, Usha2; Schildkraut, Joellen M2; Pearce, Celeste Leigh2; Cramer, Daniel W2; Rossing, Mary Anne2; Chenevix-Trench, Georgia2; Pharoah, Paul D P2; Gayther, Simon A2; Ness, Roberta B2; Odunsi, Kunle2; Sucheston, Lara E2; Knutson, Keith L2; Goode, Ellen L2
1 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.
Cancer Immunology Research (cir), 2014, Vol 2, Issue 4, p. 332-340
Female; Gene Expression; Gene Expression Profiling; Genetic Predisposition to Disease; Genetic Variation; Germ-Line Mutation; Humans; Interleukin-2 Receptor alpha Subunit; Neoplasm Grading; Neoplasm Invasiveness; Ovarian Neoplasms; Patient Outcome Assessment; Polymorphism, Single Nucleotide; Prognosis; T-Lymphocytes, Regulatory; Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.