Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

On behalf of the Australian Ovarian Cancer Study Group

doi:10.18632/oncotarget.10215

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

On behalf of the Australian Ovarian Cancer Study Group

Obstetrics & Gynecology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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	https://doi.org/10.18632/oncotarget.10215
State	Published - 2016

Keywords

Biomarkers
Genetic variation
Immunosuppression
Ovarian cancer
TGFBR2

ASJC Scopus subject areas

Oncology

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@article{d8f3a6b7c94840a59a9d7a7c10c22416,

title = "Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer",

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.",

keywords = "Biomarkers, Genetic variation, Immunosuppression, Ovarian cancer, TGFBR2",

author = "{On behalf of the Australian Ovarian Cancer Study Group} and Hampras, {Shalaka S.} and Sucheston-Campbell, {Lara E.} and Rikki Cannioto and Jenny Chang-Claude and Francesmary Modugno and Thilo D{\"o}rk and Peter Hillemanns and Leah Preus and Knutson, {Keith L.} and Wallace, {Paul K.} and Hong, {Chi Chen} and Grace Friel and Warren Davis and Mary Nesline and Pearce, {Celeste L.} and Kelemen, {Linda E.} and Goodman, {Marc T.} and Bandera, {Elisa V.} and Terry, {Kathryn L.} and Nils Schoof and Eng, {Kevin H.} and Alyssa Clay and Singh, {Prashant K.} and Joseph, {Janine M.} and Aben, {Katja K.H.} and Hoda Anton-Culver and Natalia Antonenkova and Helen Baker and Yukie Bean and Beckmann, {Matthias W.} and Maria Bisogna and Line Bjorge and Natalia Bogdanova and Brinton, {Louise A.} and Angela Brooks-Wilson and Fiona Bruinsma and Ralf Butzow and Campbell, {Ian G.} and Karen Carty and Cook, {Linda S.} and Cramer, {Daniel W.} and Cezary Cybulski and Agnieszka Dansonka-Mieszkowska and Joe Dennis and Evelyn Despierre and Ed Dicks and Doherty, {Jennifer A.} and {du Bois}, Andreas and Matthias D{\"u}rst and Tanja Pejovic",

note = "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-W?rttemberg 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.",

year = "2016",

doi = "10.18632/oncotarget.10215",

language = "English (US)",

volume = "7",

pages = "69097--69110",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals",

number = "43",

}

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 - Dürst, Matthias

AU - Pejovic, Tanja

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-W?rttemberg 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

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U2 - 10.18632/oncotarget.10215

DO - 10.18632/oncotarget.10215

M3 - Article

C2 - 27533245

AN - SCOPUS:84994344826

VL - 7

SP - 69097

EP - 69110

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 43

ER -