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. 2014 Apr;2(4):332-40.
doi: 10.1158/2326-6066.CIR-13-0136. Epub 2014 Jan 27.

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

Bridget Charbonneau  1 , 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
Affiliations

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

Bridget Charbonneau et al. Cancer Immunol Res. 2014 Apr.

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.

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Conflict of interest statement

Conflict of interest: B Charbonneau was an employee of Mayo Clinic at the time this manuscript was drafted and is currently an employee of and owns stock in Eli Lilly and Company.

Figures

Figure 1
Figure 1
Kaplan–Meier curves accounting for left-truncation for the most statistically significantly associated SNPs and overall survival in women with (A) endometrioid EOC with rs11256497 genotype [GG(N=582), AG(N=670), and AA(N=200)]; (B) clear cell EOC with rs231775 genotype [AA(N=313), AG(N=379), and GG(N=103)]; (C) high-grade serous EOC with rs6770038 genotype [GG(N=3, 484), AG(N=1,604), and AA(N=160)]; (D) mucinous EOC with rs4658265 genotype [GG(N=305), AG(N=295), and AA(N=61)]; and (E) any invasive EOC with rs4522809 genotype [AA(N=2,782), AG(N=5,069), and GG(N=2,232)].
Figure 2
Figure 2
SNPs most statistically significantly associated with overall survival in endometrioid and clear cell EOC. Association p-values (−log10(p-value)) using LocusZoom (30) of all SNPs in (A) IL2RA for endometrioid (rs11256497 represented by purple circle), (B) CTLA4 for clear cell (rs231775 represented by purple triangle), (C) TGFBR2 for high-grade serous (rs6770038 represented by purple circle), (D) TGFBR3 for mucinous (rs4658265 represented by purple circle), and (E) TGFBR2 for all invasive EOC (rs4522809 represented by purple circle). Annotation key: ▲ - framestop or splice; ▼ - NonSynonymous; ■ - Synonymous or UTR; ● – no; × - conserved in placental mammals
Figure 3
Figure 3
IL2RA mRNA expression (normalized and log10 transformed) by rs11256497 genotype in endometrioid EOC tumors. Two different Agilent IL2RA probes are presented A) A_23_P237288 and B) A_24_P230563. Two-tailed, unpaired t test p-value is reported.
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