Abstract
Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 69097-69110 |
| Number of pages | 14 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 43 |
| DOIs | |
| State | Published - 2016 |
Keywords
- Biomarkers
- Genetic variation
- Immunosuppression
- Ovarian cancer
- TGFBR2
ASJC Scopus subject areas
- Oncology
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In: Oncotarget, Vol. 7, No. 43, 2016, p. 69097-69110.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer
AU - On behalf of the Australian Ovarian Cancer Study Group
AU - Hampras, Shalaka S.
AU - Sucheston-Campbell, Lara E.
AU - Cannioto, Rikki
AU - Chang-Claude, Jenny
AU - Modugno, Francesmary
AU - Dörk, Thilo
AU - Hillemanns, Peter
AU - Preus, Leah
AU - Knutson, Keith L.
AU - Wallace, Paul K.
AU - Hong, Chi Chen
AU - Friel, Grace
AU - Davis, Warren
AU - Nesline, Mary
AU - Pearce, Celeste L.
AU - Kelemen, Linda E.
AU - Goodman, Marc T.
AU - Bandera, Elisa V.
AU - Terry, Kathryn L.
AU - Schoof, Nils
AU - Eng, Kevin H.
AU - Clay, Alyssa
AU - Singh, Prashant K.
AU - Joseph, Janine M.
AU - Aben, Katja K.H.
AU - Anton-Culver, Hoda
AU - Antonenkova, Natalia
AU - Baker, Helen
AU - Bean, Yukie
AU - Beckmann, Matthias W.
AU - Bisogna, Maria
AU - Bjorge, Line
AU - Bogdanova, Natalia
AU - Brinton, Louise A.
AU - Brooks-Wilson, Angela
AU - Bruinsma, Fiona
AU - Butzow, Ralf
AU - Campbell, Ian G.
AU - Carty, Karen
AU - Cook, Linda S.
AU - Cramer, Daniel W.
AU - Cybulski, Cezary
AU - Dansonka-Mieszkowska, Agnieszka
AU - Dennis, Joe
AU - Despierre, Evelyn
AU - Dicks, Ed
AU - Doherty, Jennifer A.
AU - du Bois, Andreas
AU - Cunningham, Julie M.
AU - Goode, Ellen L.
N1 - Funding Information: The Australian Ovarian Cancer Study Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb) and ACS Investigators (A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman) thank all the clinical and scientific collaborators (see http://www.aocstudy.org/) and the women for their contribution. The Belgian Ovarium Cancer Study wished to thank Gilian Peuteman, Thomas Van Brussel and Dominiek Smeets for technical assistance. The German Ovarian Cancer Study (GER) thanks Ursula Eilber and Tanja Koehler for competent technical assistance. The Helsinki Ovarian Cancer Study study was supported by the Helsinki University Central Hospital Reseaarch Fund. The Mayo Clinic Ovarian Cancer Case-Control Study, for iCOGS thanks C. Hilker, S. Windebank, and J. Vollenweider for iSelect genotyping. The Nurses Health Study and Nurses Health Study II thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The Study of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) thanks the SEARCH team, Craig Luccarini, Caroline Baynes, Don Conroy. Thanks to all members of Scottish Gynaecological Clinical Trails group and SCOTROC1 investigators. United Kingdom Ovarian cancer Population Study thanks I. Jacobs, M. Widschwendter, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study. The UK Familial Ovarian Cancer Registry thanks Carole Pye. This study was supported by funding from several sources including the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07); the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112 and U19-CA148537); the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175); the Canadian Institutes for Health Research (CIHR) MOP-86727 and the CIHR Team in Familial Risks of Breast Cancer; the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); 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, C536/A6689, C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692); 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; 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 US National Institutes of Health/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056; the US National Cancer Institute (RPCI-UPCI Ovarian Cancer SPORE P50CA159981-01A1, K07-CA095666, K07-K07-CA80668, CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P20-GM103418, P30-CA072720, P30-CA15083, P30-CA168524, P30-CA008748, 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-CA128978, 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, CA58860, CA92044, PSA042205, UM1-CA186107, P01-CA87969, R01-CA49449, UM1-CA176726, R01-CA67262 and Intramural research funds); National Institute of Environmental Health Sciences (T32ES013678); the US Department of Defense Ovarian Cancer Research Program (W81XWH-07-0449); the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280, W81XWH-10-1-0341); 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-Württemberg 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 UK 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; WorkSafeBC; Komen Foundation for the Cure; and the Breast Cancer Research Foundation; the Lon V Smith Foundation grant LVS-39420. G. Chenevix-Trench and P.M. Webb are supported by the Australian National Health and Medical Research Council; B. Karlan holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN); and A. Berchuck holds the Barbara Thomason Ovarian Cancer Research Professorship from the American Cancer Society (SIOP-06-090-06). Cytometry services were provided by the Flow and Image Cytometry Core facility at the Roswell Park Cancer Institute which is supported in part by the NCI Cancer Center Support Grant 5P30 CA016056.
PY - 2016
Y1 - 2016
N2 - Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
AB - Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
KW - Biomarkers
KW - Genetic variation
KW - Immunosuppression
KW - Ovarian cancer
KW - TGFBR2
UR - http://www.scopus.com/inward/record.url?scp=84994344826&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994344826&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.10215
DO - 10.18632/oncotarget.10215
M3 - Article
C2 - 27533245
AN - SCOPUS:84994344826
SN - 1949-2553
VL - 7
SP - 69097
EP - 69110
JO - Oncotarget
JF - Oncotarget
IS - 43
ER -