Large-Scale Evaluation of Common Variation in Regulatory T Cell Genes and Ovarian Cancer Outcome
The presence of regulatory T cells (Tregs) in solid tumors is known to play a role in patient survival in ovarian cancer and a number of other malignancies. We assessed inherited genetic variation via 749 tag SNPs 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% CI: 1.22-1.64; p=5.7 x 10-6], rs791587 [HR=1.36, 95% CI:1.17-1.57; p=6.2 x 10-5], rs2476491 [HR=1.40, 95% CI: 1.19-1.64; p=5.6 x 10-5], and rs10795763 [HR=1.35, 95% CI: 1.17-1.57; p=7.9 x 10-5], and for clear cell carcinoma and CTLA4 SNP rs231775 [HR=0.67, 95% CI: 0.54-0.82; p=9.3 x 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 has previously been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs appear to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid EOC.
- Received August 28, 2013.
- Revision received December 12, 2013.
- Accepted December 20, 2013.
- Copyright © 2014, American Association for Cancer Research.
Published OnlineFirst January 27, 2014