Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome
Authors: Charbonneau Bridget , Moysich Kirsten B. , Kalli Kimberly R. , Oberg Ann L. , Vierkant Robert A. , Fogarty Zachary C. , Block Matthew S. , Maurer Matthew J. , Goergen Krista M. , Fridley Brooke L. , Cunningham Julie M. , Rider David N. , Preston Claudia , Hartmann Lynn C. , Lawrenson Kate , Wang Chen , Tyrer Jonathan , Song Honglin , deFazio Anna , Johnatty Sharon E. , Doherty Jennifer A. , Phelan Catherine M. , Sellers Thomas A. , Ramirez Starr M. , Vitonis Allison F. , Terry Kathryn L. , Van Den Berg David , Pike Malcolm C. , Wu Anna H. , Berchuck Andrew , Gentry-Maharaj Aleksandra , Ramus Susan J. , Diergaarde Brenda , Shen Howard , Jensen Allan , Menkiszak Janusz , Cybulski Cezary , Lubiński Jan , Ziogas Argyrios , Rothstein Joseph H. , McGuire Valerie , Sieh Weiva , Lester Jenny , Walsh Christine , Vergote Ignace , Lambrechts Sandrina , Despierre Evelyn , Garcia-Closas Montserrat , Yang Hannah , Brinton Louise A. , Spiewankiewicz Beata , Rzepecka Iwona K. , Dansonka-Mieszkowska Agnieszka , Seibold Petra , Rudolph Anja , Paddock Lisa E. , Orlow Irene , Lundvall Lene , Olson Sara H. , Hogdall Claus K. , Schwaab Ira , du Bois Andreas , Harter Philipp , Flanagan James M. , Brown Robert , Paul James , Ekici Arif B. , Beckmann Matthias W. , Hein Alexander , Eccles Diana , Lurie Galina , Hays Laura E. , Bean Yukie T. , Pejovic Tanja , Goodman Marc T. , Campbell Ian , Fasching Peter A. , Konecny Gottfried , Kaye Stanley B. , Heitz Florian , Hogdall Estrid , Bandera Elisa V. , Chang-Claude Jenny , Kupryjanczyk Jolanta , Wentzensen Nicolas , Lambrechts Diether , Karlan Beth Y. , Whittemore Alice S. , Culver Hoda Anton , Gronwald Jacek , Levine Douglas A. , Kjaer Susanne K. , Menon Usha , Schildkraut Joellen M. , Pearce Celeste Leigh , Cramer Daniel W. , Rossing Mary Anne , Chenevix-Trench Georgia ,   for the AOCS group,   ACS, Pharoah Paul D.P. , Gayther Simon A. , Ness Roberta B. , Odunsi Kunle , Sucheston Lara E. , Knutson Keith L. , Goode Ellen L. 
Published: January 2014

Abstract
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 Immunol Res; 2(4); 332–40. ©2014 AACR.