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 rs 10795763(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) 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 332-340 |
| Number of pages | 9 |
| Journal | Cancer Immunology Research |
| Volume | 2 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2014 |
ASJC Scopus subject areas
- Medicine(all)
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In: Cancer Immunology Research, Vol. 2, No. 4, 04.2014, p. 332-340.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome
AU - OCS Group ACS
AU - Charbonneau, Bridget
AU - Moysich, Kirsten B.
AU - Kalli, Kimberly R.
AU - Oberg, Ann L.
AU - Vierkant, Robert A.
AU - Fogarty, Zachary C.
AU - Block, Matthew S.
AU - Maurer, Matthew J.
AU - Goergen, Krista M.
AU - Fridley, Brooke L.
AU - Cunningham, Julie M.
AU - Rider, David N.
AU - Preston, Claudia
AU - Hartmann, Lynn C.
AU - Lawrenson, Kate
AU - Wang, Chen
AU - Tyrer, Jonathan
AU - Song, Honglin
AU - De Fazio, Anna
AU - Johnatty, Sharon E.
AU - Doherty, Jennifer A.
AU - Phelan, Catherine M.
AU - Sellers, Thomas A.
AU - Ramirez, Starr M.
AU - Vitonis, Allison F.
AU - Terry, Kathryn L.
AU - Van Den Berg, David
AU - Pike, Malcolm C.
AU - Wu, Anna H.
AU - Berchuck, Andrew
AU - Gentry-Maharaj, Aleksandra
AU - Ramus, Susan J.
AU - Diergaarde, Brenda
AU - Shen, Howard
AU - Jensen, Allan
AU - Menkiszak, Janusz
AU - Cybulski, Cezary
AU - Lubinski, Jan
AU - Ziogas, Argyrios
AU - Rothstein, Joseph H.
AU - McGuire, Valerie
AU - Sieh, Weiva
AU - Lester, Jenny
AU - Walsh, Christine
AU - Vergote, Ignace
AU - Lambrechts, Sandrina
AU - Despierre, Evelyn
AU - Garcia-Closas, Montserrat
AU - Yang, Hannah
AU - Pejovic, Tanja
N1 - Funding Information: Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175; COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692), the NIH (R01-CA128978) and its Post-Cancer GWAS initiative (No. 1 U19-CA148537 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, and the Breast Cancer Research Foundation, and CIHR MOP-86727. Funding Information: Funding of the constituent OCAC studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, and 2II0200); the Canadian Institutes for Health Research; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/ A13086, and C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; The Eve Appeal (Oak Foundation); the Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education; the U.S. National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P20-GM103418, P30-CA072720, P30-CA15083, P30-CA168524, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA61107, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R21-GM86689, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, and Intramural research funds); the U.S. Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, and W81XWH-10-1-0280); the National Health and Medical Research Council of Australia (199600, 400413, and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Polish Committee for Scientific Research (4P05C 028 14 and 2P05A 068 27); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the U.K. National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital "Womens Health Theme" and the Royal Marsden Hospital; and WorkSafeBC. Funding Information: The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112). G. Chenevix-Trench and P.M. Webb are supported by the National Health and Medical Research Council. B.Y. Karlan holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). B. Charbonneau was supported by R25 CA92049. Andrew Berchuck holds the Barbara Thomason Ovarian Cancer Research Professorship from the American Cancer Society (SIOP-06-090-06). Funding of the constituent OCAC studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, and 2II0200); the Canadian Institutes for Health Research; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/A13086, and C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; The Eve Appeal (Oak Foundation); the Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education; the U.S. National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P20-GM103418, P30-CA072720, P30-CA15083, P30-CA168524, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA61107, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R21-GM86689, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, and Intramural research funds); the U.S. Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-021-0669, and W81XWH-10-1-0280); the National Health and Medical Research Council of Australia (199600, 400413, and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Polish Committee for Scientific Research (4P05C 028 14 and 2P05A 068 27); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the U.K. National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital "Womens Health Theme" and the Royal Marsden Hospital; and WorkSafeBC. Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTHF2-2009-223175; COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692), the NIH (R01-CA128978) and its Post-Cancer GWAS initiative (No. 1 U19-CA148537 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, and the Breast Cancer Research Foundation, and CIHR MOP-86727. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Funding Information: The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112). G. Chenevix-Trench and P.M. Webb are supported by the National Health and Medical Research Council. B.Y. Karlan holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). B. Char-bonneau was supported by R25 CA92049. Andrew Berchuck holds the Barbara Thomason Ovarian Cancer Research Professorship from the American Cancer Society (SIOP-06-090-06). Publisher Copyright: © 2014 American Association for Cancer Research.
PY - 2014/4
Y1 - 2014/4
N2 - 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 rs 10795763(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) 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.
AB - 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 rs 10795763(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) 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.
UR - http://www.scopus.com/inward/record.url?scp=84905051761&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905051761&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-13-0136
DO - 10.1158/2326-6066.CIR-13-0136
M3 - Article
C2 - 24764580
AN - SCOPUS:84905051761
SN - 2326-6066
VL - 2
SP - 332
EP - 340
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 4
ER -