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Oncotarget. 2016 Oct 25;7(43):69097-69110. doi: 10.18632/oncotarget.10215.

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

Hampras SS1, Sucheston-Campbell LE2,3, Cannioto R4, Chang-Claude J5, Modugno F6,7, Dörk T8, Hillemanns P9, Preus L4, Knutson KL10, Wallace PK11, Hong CC4, Friel G4, Davis W4, Nesline M12, Pearce CL13, Kelemen LE14, Goodman MT15, Bandera EV16, Terry KL17, Schoof N18, Eng KH19, Clay A4, Singh PK4, Joseph JM4, Aben KK20, Anton-Culver H21, Antonenkova N22, Baker H23, Bean Y24, Beckmann MW25, Bisogna M26, Bjorge L27, Bogdanova N8, Brinton LA28, Brooks-Wilson A29, Bruinsma F30, Butzow R31, Campbell IG32, Carty K33, Cook LS34, Cramer DW17, Cybulski C35, Dansonka-Mieszkowska A36, Dennis J23, Despierre E37, Dicks E23, Doherty JA38, du Bois A39, Dürst M40, Easton D41, Eccles D42, Edwards RP43, Ekici AB44, Fasching PA45, Fridley BL46, Gao YT47, Gentry-Maharaj A48, Giles GG30,49, Glasspool R33, Gronwald J50, Harrington P23, Harter P39, Hasmad HN51, Hein A25, Heitz F39, Hildebrandt MA52, Hogdall C53, Hogdall E54, Hosono S55, Iversen ES56, Jakubowska A50, Jensen A57, Ji BT28, Karlan BY58, Kellar M24, Kelley JL59, Kiemeney LA20, Klapdor R8, Kolomeyevskaya N60, Krakstad C27, Kjaer SK53,57, Kruszka B4, Kupryjanczyk J36, Lambrechts D61,62, Lambrechts S37, Le ND63, Lee AW13, Lele S60, Leminen A31, Lester J58, Levine DA26, Liang D64, Lissowska J65, Liu S19, Lu K65, Lubinski J49, Lundvall L53, Massuger LF66, Matsuo K55, McGuire V67, McLaughlin JR68, McNeish I69, Menon U70, Moes-Sosnowska J36, Narod SA71, Nedergaard L72, Nevanlinna H31, Nickels S5, Olson SH73, Orlow I74, Weber RP75, Paul J33, Pejovic T23, Pelttari LM31, Perkins B23, Permuth-Wey J1, Pike MC13,73, Plisiecka-Halasa J36, Poole EM76, Risch HA77, Rossing MA78, Rothstein JH67, Rudolph A5, Runnebaum IB40, Rzepecka IK36, Salvesen HB27, Schernhammer E75, Schmitt K4, Schwaab I79, Shu XO80, Shvetsov YB81, Siddiqui N82, Sieh W67, Song H23, Southey MC83, Tangen IL27, Teo SH84, Thompson PJ15, Timorek A85, Tsai YY1, Tworoger SS76, Tyrer J23, van Altena AM66, Vergote I37, Vierkant RA86, Walsh C58, Wang-Gohrke S5, Wentzensen N28, Whittemore AS67, Wicklund KG78, Wilkens LR81, Wu AH13, Wu X52, Woo YL87, Yang H28, Zheng W80, Ziogas A21, Gayther SA13, Ramus SJ13, Sellers TA1, Schildkraut JM75, Phelan CM1, Berchuck A88, Chenevix-Trench G89,90, Cunningham JM91, Pharoah PP41, Ness RB92, Odunsi K60, Goode EL93, Moysich KB4.

Author information

1
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA.
2
College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
3
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
4
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
5
German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany.
6
Department of Epidemiology and Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
7
Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
8
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
9
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
10
Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
11
Department of Flow & Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USA.
12
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
13
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
14
Alberta Health Services-Cancer Care, Department of Population Health Research, Calgary, Alberta, Canada.
15
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
16
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.
17
Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
18
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
19
Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, USA.
20
Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands.
21
Department of Epidemiology and School of Medicine, University of California Irvine, Irvine, California, USA.
22
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.
23
Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
24
Department of Obstetrics & Gynecology and Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
25
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
26
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
27
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
28
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
29
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
30
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
31
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
32
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Australia.
33
Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK.
34
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
35
International Hereditary Cancer Center, Department of Genetics and Pathology, Clinic of Opthalmology, Pomeranian Medical University, Szczecin, Poland.
36
Department of Pathology and Labolatory Diagnostic, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
37
Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, Belgium.
38
Department of Community and Family Medicine, Section of Biostatistics & Epidemiology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
39
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen, Germany.
40
Department of Gynecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany.
41
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
42
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
43
Department of Obstetrics, Gynecology & Reproductive Sciences and Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
44
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
45
Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, USA.
46
Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, USA,.
47
Shanghai Cancer Institute, Shanghai, China.
48
Institute for Women's Health, Population Health Sciences, University College - London, London, United Kingdom.
49
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
50
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
51
Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia.
52
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
53
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
54
Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
55
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
56
Department of Statistical Science, Duke University, Durham, North Carolina, USA.
57
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
58
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
59
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
60
Division of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
61
Vesalius Research Center, VIB, Leuven, Belgium,.
62
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Belgium.
63
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
64
College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA.
65
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
66
Department of Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
67
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, USA.
68
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
69
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
70
Women's Cancer, UCL EGA Institute for Women's Health, London, UK.
71
Women's College Research Institute, Toronto, Ontario, Canada.
72
Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark.
73
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
74
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA,.
75
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA.
76
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
77
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.
78
Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
79
Institut für Humangenetik Wiesbaden, Wiesbaden, Germany.
80
Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
81
Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA.
82
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, Scotland, UK.
83
Department of Pathology, The University of Melbourne, Melbourne, Australia.
84
Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia,.
85
Department of Obstetrics, Gynecology and Oncology, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.
86
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
87
Department of Obstetrics and Gynaecology, Affiliated with UM Cancer Research Institute, Faculty of Medicine, University of Malaya, Malaysia.
88
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA.
89
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
90
On behalf of the Australian Ovarian Cancer Study Group.
91
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
92
School of Public Health, The University of Texas, Houston, Texas, USA.
93
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.

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:

TGFBR2 ; biomarkers; genetic variation; immunosuppression; ovarian cancer

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