Fulltext

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

Hampras SS 1 , Sucheston-Campbell LE 2 , Cannioto R 3 , Chang-Claude J 4 , Modugno F 5 , Dörk T 6 Show all authors , Hillemanns P 7 , Preus L 3 , Knutson KL 8 , Wallace PK 9 , Hong CC 3 , Friel G 3 , Davis W 3 , Nesline M 10 , Pearce CL 11 , Kelemen LE 12 , Goodman MT 13 , Bandera EV 14 , Terry KL 15 , Schoof N 16 , Eng KH 17 , Clay A 3 , Singh PK 3 , Joseph JM 3 , Aben KK 18 , Anton-Culver H 19 , Antonenkova N 20 , Baker H 21 , Bean Y 22 , Beckmann MW 23 , Bisogna M 24 , Bjorge L 25 , Bogdanova N 6 , Brinton LA 26 , Brooks-Wilson A 27 , Bruinsma F 28 , Butzow R 29 , Campbell IG 30 , Carty K 31 , Cook LS 32 , Cramer DW 15 , Cybulski C 33 , Dansonka-Mieszkowska A 34 , Dennis J 21 , Despierre E 35 , Dicks E 21 , Doherty JA 36 , du Bois A 37 , Dürst M 38 , Easton D 39 , Eccles D 40 , Edwards RP 41 , Ekici AB 42 , Fasching PA 43 , Fridley BL 44 , Gao YT 45 , Gentry-Maharaj A 46 , Giles GG 28 , Glasspool R 31 , Gronwald J 47 , Harrington P 21 , Harter P 37 , Hasmad HN 48 , Hein A 23 , Heitz F 37 , Hildebrandt MA 49 , Hogdall C 50 , Hogdall E 51 , Hosono S 52 , Iversen ES 53 , Jakubowska A 47 , Jensen A 54 , Ji BT 26 , Karlan BY 55 , Kellar M 22 , Kelley JL 56 , Kiemeney LA 18 , Klapdor R 6 , Kolomeyevskaya N 57 , Krakstad C 25 , Kjaer SK 50 , Kruszka B 3 , Kupryjanczyk J 34 , Lambrechts D 58 , Lambrechts S 35 , Le ND 59 , Lee AW 11 , Lele S 57 , Leminen A 29 , Lester J 55 , Levine DA 24 , Liang D 60 , Lissowska J 61 , Liu S 17 , Lu K 61 , Lubinski J 62 , Lundvall L 50 , Massuger LF 63 , Matsuo K 52 , McGuire V 64 , McLaughlin JR 65 , McNeish I 66 , Menon U 67 , Moes-Sosnowska J 34 , Narod SA 68 , Nedergaard L 69 , Nevanlinna H 29 , Nickels S 4 , Olson SH 70 , Orlow I 71 , Weber RP 72 , Paul J 31 , Pejovic T 21 , Pelttari LM 29 , Perkins B 21 , Permuth-Wey J 1 , Pike MC 11 , Plisiecka-Halasa J 34 , Poole EM 73 , Risch HA 74 , Rossing MA 75 , Rothstein JH 64 , Rudolph A 4 , Runnebaum IB 38 , Rzepecka IK 34 , Salvesen HB 25 , Schernhammer E 72 , Schmitt K 3 , Schwaab I 76 , Shu XO 77 , Shvetsov YB 78 , Siddiqui N 79 , Sieh W 64 , Song H 21 , Southey MC 80 , Tangen IL 25 , Teo SH 81 , Thompson PJ 13 , Timorek A 82 , Tsai YY 1 , Tworoger SS 73 , Tyrer J 21 , van Altena AM 63 , Vergote I 35 , Vierkant RA 83 , Walsh C 55 , Wang-Gohrke S 4 , Wentzensen N 26 , Whittemore AS 64 , Wicklund KG 75 , Wilkens LR 78 , Wu AH 11 , Wu X 49 , Woo YL 84 , Yang H 26 , Zheng W 77 , Ziogas A 19 , Gayther SA 11 , Ramus SJ 11 , Sellers TA 1 , Schildkraut JM 72 , Phelan CM 1 , Berchuck A 85 , Chenevix-Trench G 86 , Cunningham JM 87 , Pharoah PP 39 , Ness RB 88 , Odunsi K 57 , Goode EL 89 , Moysich KB 3

Affiliations 

  • 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 Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
  • 4 German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
  • 5 Department of Epidemiology and Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  • 6 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 7 Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany
  • 8 Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
  • 9 Department of Flow & Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USA
  • 10 Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
  • 11 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA
  • 12 Alberta Health Services-Cancer Care, Department of Population Health Research, Calgary, Alberta, Canada
  • 13 Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  • 14 Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
  • 15 Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  • 16 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 17 Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, USA
  • 18 Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands
  • 19 Department of Epidemiology and School of Medicine, University of California Irvine, Irvine, California, USA
  • 20 Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus
  • 21 Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
  • 22 Department of Obstetrics & Gynecology and Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
  • 23 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • 24 Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
  • 25 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
  • 26 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
  • 27 Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
  • 28 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
  • 29 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
  • 30 Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Australia
  • 31 Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK
  • 32 Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA
  • 33 International Hereditary Cancer Center, Department of Genetics and Pathology, Clinic of Opthalmology, Pomeranian Medical University, Szczecin, Poland
  • 34 Department of Pathology and Labolatory Diagnostic, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 35 Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, Belgium
  • 36 Department of Community and Family Medicine, Section of Biostatistics & Epidemiology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
  • 37 Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen, Germany
  • 38 Department of Gynecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany
  • 39 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 40 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
  • 41 Department of Obstetrics, Gynecology & Reproductive Sciences and Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  • 42 Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • 43 Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, USA
  • 44 Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, USA,
  • 45 Shanghai Cancer Institute, Shanghai, China
  • 46 Institute for Women's Health, Population Health Sciences, University College - London, London, United Kingdom
  • 47 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 48 Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia
  • 49 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  • 50 Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 51 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
  • 52 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
  • 53 Department of Statistical Science, Duke University, Durham, North Carolina, USA
  • 54 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 55 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  • 56 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  • 57 Division of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
  • 58 Vesalius Research Center, VIB, Leuven, Belgium,
  • 59 Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada
  • 60 College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA
  • 61 Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 62 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
  • 63 Department of Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • 64 Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, USA
  • 65 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  • 66 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
  • 67 Women's Cancer, UCL EGA Institute for Women's Health, London, UK
  • 68 Women's College Research Institute, Toronto, Ontario, Canada
  • 69 Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark
  • 70 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  • 71 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA,
  • 72 Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA
  • 73 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  • 74 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
  • 75 Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  • 76 Institut für Humangenetik Wiesbaden, Wiesbaden, Germany
  • 77 Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  • 78 Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA
  • 79 Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, Scotland, UK
  • 80 Department of Pathology, The University of Melbourne, Melbourne, Australia
  • 81 Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia,
  • 82 Department of Obstetrics, Gynecology and Oncology, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland
  • 83 Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
  • 84 Department of Obstetrics and Gynaecology, Affiliated with UM Cancer Research Institute, Faculty of Medicine, University of Malaya, Malaysia
  • 85 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA
  • 86 Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 87 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  • 88 School of Public Health, The University of Texas, Houston, Texas, USA
  • 89 Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
Oncotarget, 2016 10 25;7(43):69097-69110.
PMID: 27533245 DOI: 10.18632/oncotarget.10215

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

MeSH terms
Similar publications