Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

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.

• Authors: Bridget Charbonneau, Kirsten B Moysich, Kimberly R Kalli, Ann L Oberg, Robert A Vierkant, Zachary C Fogarty, Matthew S Block, Matthew J Maurer, Krista M Goergen, Brooke L Fridley, Julie M Cunningham, David N Rider, Claudia Preston, Lynn C Hartmann, Kate Lawrenson, Chen Wang, Jonathan Tyrer, Honglin Song, Anna deFazio, Sharon E Johnatty, Jennifer A Doherty, Catherine M Phelan, Thomas A Sellers, Starr M Ramirez, Allison F Vitonis, Kathryn L Terry, David Van Den Berg, Malcolm C Pike, Anna H Wu, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susan J Ramus, Brenda Diergaarde, Howard Shen, Allan Jensen, Janusz Menkiszak, Cezary Cybulski, Jan Lubiłski, Argyrios Ziogas, Joseph H Rothstein, Valerie McGuire, Weiva Sieh, Jenny Lester, Christine Walsh, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Montserrat Garcia-Closas, Hannah Yang, Louise A Brinton, Beata Spiewankiewicz, Iwona K Rzepecka, Agnieszka Dansonka-Mieszkowska, Petra Seibold, Anja Rudolph, Lisa E Paddock, Irene Orlow, Lene Lundvall, Sara H Olson, Claus K Hogdall, Ira Schwaab, Andreas du Bois, Philipp Harter, James M Flanagan, Robert Brown, James Paul, Arif B Ekici, Matthias W Beckmann, Alexander Hein, Diana Eccles, Galina Lurie, Laura E Hays, Yukie T Bean, Tanja Pejovic, Marc T Goodman, Ian Campbell, Peter A Fasching, Gottfried Konecny, Stanley B Kaye, Florian Heitz, Estrid Hogdall, Elisa V Bandera, Jenny Chang-Claude, Jolanta Kupryjanczyk, Nicolas Wentzensen, Diether Lambrechts, Beth Y Karlan, Alice S Whittemore, Hoda Anton Culver, Jacek Gronwald, Douglas A Levine, Susanne K Kjaer, Usha Menon, Joellen M Schildkraut, Celeste Leigh Pearce, Daniel W Cramer, Mary Anne Rossing, Georgia Chenevix-Trench, AOCS group, ACS, Paul D P Pharoah, Simon A Gayther, Roberta B Ness, Kunle Odunsi, Lara E Sucheston, Keith L Knutson, Ellen L Goode
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 2 Issue 4 Pg. 332-40 (Apr 2014) ISSN: 2326-6074 [Electronic] United States
• PMID: 24764580 (Publication Type: 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.)

Chemical References

• Interleukin-2 Receptor alpha Subunit

Topics

• Female
• Gene Expression
• Gene Expression Profiling
• Genetic Predisposition to Disease
• Genetic Variation
• Germ-Line Mutation
• Humans
• Interleukin-2 Receptor alpha Subunit (genetics)
• Neoplasm Grading
• Neoplasm Invasiveness
• Ovarian Neoplasms (genetics, mortality, pathology)
• Patient Outcome Assessment
• Polymorphism, Single Nucleotide
• Prognosis
• T-Lymphocytes, Regulatory (metabolism)