Oncotarget

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

Shalaka S. Hampras _, Lara E. Sucheston-Campbell, Rikki Cannioto, Jenny Chang-Claude, Francesmary Modugno, Thilo Dörk, Peter Hillemanns, Leah Preus, Keith L. Knutson, Paul K. Wallace, Chi-Chen Hong, Grace Friel, Warren Davis, Mary Nesline, Celeste L. Pearce, Linda E. Kelemen, Marc T. Goodman, Elisa V. Bandera, Kathryn L. Terry, Nils Schoof, Kevin H. Eng, Alyssa Clay, Prashant K. Singh, Janine M. Joseph, Katja K.H. Aben, Hoda Anton-Culver, Natalia Antonenkova, Helen Baker, Yukie Bean, Matthias W. Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A. Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G. Campbell, Karen Carty, Linda S. Cook, Daniel W. Cramer, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Joe Dennis, Evelyn Despierre, Ed Dicks, Jennifer A. Doherty, Andreas du Bois, Matthias Dürst, Doug Easton, Diana Eccles, Robert P. Edwards, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind Glasspool, Jacek Gronwald, Patricia Harrington, Philipp Harter, Hanis Nazihah Hasmad, Alexander Hein, Florian Heitz, Michelle A.T. Hildebrandt, Claus Hogdall, Estrid Hogdall, Satoyo Hosono, Edwin S. Iversen, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y. Karlan, Melissa Kellar, Joseph L. Kelley, Lambertus A. Kiemeney, Rüdiger Klapdor, Nonna Kolomeyevskaya, Camilla Krakstad, Susanne K. Kjaer, Bridget Kruszka, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Alice W. Lee, Shashikant Lele, Arto Leminen, Jenny Lester, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Song Liu, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F.A.G. Massuger, Keitaro Matsuo, Valeria McGuire, John R. McLaughlin, Ian McNeish, Usha Menon, Joanna Moes-Sosnowska, Steven A. Narod, Lotte Nedergaard, Heli Nevalinna, Stefan Nickels, Lotte Nedergaard, Heli Nevanlinna, Stefan Nickels, Sara H. Olson, Irene Orlow, Rachel Palmieri Weber, James Paul, Tanja Pejovic, Liisa M. Pelttari, Barbara Perkins, Jenny Permuth-Wey, Malcolm C. Pike, Joanna Plisiecka-Halasa, Elizabeth M. Poole, Harvey A. Risch, Mary Anne Rossing, Joseph H. Rothstein, Anja Rudolph, Ingo B. Runnebaum, Iwona K. Rzepecka, Helga B. Salvesen, Eva Schernhammer, Kristina Schmitt, Ira Schwaab, Xiao-Ou Shu, Yurii B. Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Ingvild L. Tangen, Soo-Hwang Teo, Pamela J. Thompson, Agnieszka Timorek, Ya-Yu Tsai, Shelley S. Tworoger, Jonathan Tyrer, Anna M. van Altena, Ignace Vergote, Robert A. Vierkant, Christine Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S. Whittemore, Kristine G. Wicklund, Lynne R. Wilkens, Anna H. Wu, Xifeng Wu, Yin-Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Simon A. Gayther, Susan J. Ramus, Thomas A. Sellers, Joellen M. Schildkraut, Catherine M. Phelan, Andrew Berchuck, Georgia Chenevix-Trench, Julie M. Cunningham, Paul P. Pharoah, Roberta B. Ness, Kunle Odunsi, Ellen L. Goode and Kirsten B. Moysich

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Oncotarget. 2016; 7:69097-69110. https://doi.org/10.18632/oncotarget.10215

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Abstract

Shalaka S. Hampras 1,* , Lara E. Sucheston-Campbell 2,3,*, Rikki Cannioto 4, Jenny Chang-Claude 5, Francesmary Modugno 6,7, Thilo Dörk 8, Peter Hillemanns 9, Leah Preus 4, Keith L. Knutson 10, Paul K.Wallace 11, Chi-Chen Hong 4, Grace Friel 4, Warren Davis 4, Mary Nesline 12, Celeste L. Pearce 13, Linda E. Kelemen 14, Marc T. Goodman 15, Elisa V. Bandera 16, Kathryn L. Terry 17, Nils Schoof 18, Kevin H. Eng 19, Alyssa Clay 4, Prashant K. Singh 4, Janine M. Joseph 4, Katja K.H. Aben 20, Hoda Anton-Culver 21, Natalia Antonenkova 22, Helen Baker 23, Yukie Bean 24, Matthias W. Beckmann 25, Maria Bisogna 26, Line Bjorge 27, Natalia Bogdanova 8, Louise A. Brinton 28, Angela Brooks-Wilson 29, Fiona Bruinsma 30, Ralf Butzow 31, Ian G. Campbell 32, Karen Carty 33, Linda S. Cook 34, Daniel W. Cramer 17, Cezary Cybulski 35, Agnieszka Dansonka-Mieszkowska 36, Joe Dennis 23, Evelyn Despierre 37, Ed Dicks 23, Jennifer A. Doherty 38, Andreas du Bois 39, Matthias Dürst 40, Doug Easton 41, Diana Eccles 42, Robert P. Edwards 43, Arif B. Ekici 44, Peter A. Fasching 45, Brooke L. Fridley 46, Yu-Tang Gao 47, Aleksandra Gentry-Maharaj 48, Graham G. Giles 30,49, Rosalind Glasspool 33, Jacek Gronwald 50, Patricia Harrington 23, Philipp Harter 39, Hanis Nazihah Hasmad 51, Alexander Hein 25, Florian Heitz 39, Michelle A.T. Hildebrandt 52, Claus Hogdall 53, Estrid Hogdall 54, Satoyo Hosono 55, Edwin S. Iversen 56, Anna Jakubowska 50, Allan Jensen 57, Bu-Tian Ji 28, Beth Y. Karlan 58, Melissa Kellar 24, Joseph L. Kelley 59, Lambertus A. Kiemeney 20, Rüdiger Klapdor 8, Nonna Kolomeyevskaya 60, Camilla Krakstad 27, Susanne K. Kjaer 53,57, Bridget Kruszka 4, Jolanta Kupryjanczyk 36, Diether Lambrechts 61,62, Sandrina Lambrechts 37, Nhu D. Le 63, Alice W. Lee 13, Shashikant Lele 60, Arto Leminen 31, Jenny Lester 58, Douglas A. Levine 26, Dong Liang 64, Jolanta Lissowska 65, Song Liu 19, Karen Lu 66, Jan Lubinski 49, Lene Lundvall 53, Leon F.A.G. Massuger 67, Keitaro Matsuo 55, Valeria McGuire 68, John R. McLaughlin 69, Ian McNeish 70, Usha Menon 71, Joanna Moes-Sosnowska 36, Steven A. Narod 72, Lotte Nedergaard 73, Heli Nevanlinna 31, Stefan Nickels 5, Sara H. Olson 74, Irene Orlow 74, Rachel Palmieri Weber 75, James Paul 33, Tanja Pejovic 23, Liisa M. Pelttari 31, Barbara Perkins 23, Jenny Permuth-Wey 1, Malcolm C. Pike 13,74, Joanna Plisiecka-Halasa 36, Elizabeth M. Poole 76, Harvey A. Risch 77, Mary Anne Rossing 78, Joseph H. Rothstein 68, Anja Rudolph 5, Ingo B. Runnebaum 40, Iwona K. Rzepecka 36, Helga B. Salvesen 27, Eva Schernhammer 75, Kristina Schmitt 4, Ira Schwaab 79, Xiao-Ou Shu 80, Yurii B Shvetsov 81, Nadeem Siddiqui 82, Weiva Sieh 68, Honglin Song 23, Melissa C. Southey 83, Ingvild L. Tangen 27, Soo-Hwang Teo 51, Pamela J. Thompson 15, Agnieszka Timorek 84, Ya-Yu Tsai 1, Shelley S. Tworoger 76, Jonathan Tyrer 23, Anna M. van Altena 67, Ignace Vergote 37, Robert A. Vierkant 85, Christine Walsh 58, Shan Wang-Gohrke 5, Nicolas Wentzensen 28, Alice S. Whittemore 68, Kristine G. Wicklund 78, Lynne R. Wilkens 81, Anna H. Wu 13, Xifeng Wu 52, Yin-Ling Woo 86, Hannah Yang 28, Wei Zheng 80, Argyrios Ziogas 21, Simon A. Gayther 13, Susan J. Ramus 13, Thomas A. Sellers 1, Joellen M. Schildkraut 75, Catherine M. Phelan 1, Andrew Berchuck 87, Georgia Chenevix-Trench 88,92, Julie M. Cunningham 89, Paul P. Pharoah 41, Roberta B. Ness 90, Kunle Odunsi 60, Ellen L. Goode 91 and Kirsten B. Moysich 4

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 Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

67 Department of Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

68 Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, USA

69 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

70 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

71 Women’s Cancer, UCL EGA Institute for Women’s Health, London, UK

72 Women’s College Research Institute, Toronto, Ontario, Canada

73 Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark

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 Department of Obstetrics, Gynecology and Oncology, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland

85 Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA

86 Department of Obstetrics and Gynaecology, Affiliated with UM Cancer Research Institute, Faculty of Medicine, University of Malaya, Malaysia

87 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA

88 Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia

89 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

90 School of Public Health, The University of Texas, Houston, Texas, USA

91 Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA

92 On behalf of the Australian Ovarian Cancer Study Group

* These authors have contributed equally to this work

Correspondence:

Kirsten B. Moysich, email:

Keywords: ovarian cancer, immunosuppression, biomarkers, genetic variation, TGFBR2

Received: March 18, 2016 Accepted: May 29, 2016 Published: June 21, 2016

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.


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