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Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Chornokur G 1 , Lin HY 2 , Tyrer JP 3 , Lawrenson K 4 , Dennis J 3 , Amankwah EK 5 Show all authors , Qu X 2 , Tsai YY 1 , Jim HS 6 , Chen Z 2 , Chen AY 2 , Permuth-Wey J 1 , Aben KK 7 , Anton-Culver H 8 , Antonenkova N 9 , Bruinsma F 10 , Bandera EV 11 , Bean YT 12 , Beckmann MW 13 , Bisogna M 14 , Bjorge L 15 , Bogdanova N 16 , Brinton LA 17 , Brooks-Wilson A 18 , Bunker CH 19 , Butzow R 20 , Campbell IG 21 , Carty K 22 , Chang-Claude J 23 , Cook LS 24 , Cramer DW 25 , Cunningham JM 26 , Cybulski C 27 , Dansonka-Mieszkowska A 28 , du Bois A 29 , Despierre E 30 , Dicks E 3 , Doherty JA 31 , Dörk T 32 , Dürst M 33 , Easton DF 34 , Eccles DM 35 , Edwards RP 36 , Ekici AB 37 , Fasching PA 38 , Fridley BL 39 , Gao YT 40 , Gentry-Maharaj A 41 , Giles GG 42 , Glasspool R 43 , Goodman MT 44 , Gronwald J 27 , Harrington P 45 , Harter P 29 , Hein A 13 , Heitz F 29 , Hildebrandt MA 46 , Hillemanns P 32 , Hogdall CK 47 , Hogdall E 48 , Hosono S 49 , Jakubowska A 27 , Jensen A 50 , Ji BT 17 , Karlan BY 51 , Kelemen LE 52 , Kellar M 12 , Kiemeney LA 53 , Krakstad C 15 , Kjaer SK 54 , Kupryjanczyk J 28 , Lambrechts D 55 , Lambrechts S 30 , Le ND 56 , Lee AW 4 , Lele S 57 , Leminen A 58 , Lester J 51 , Levine DA 14 , Liang D 59 , Lim BK 60 , Lissowska J 61 , Lu K 62 , Lubinski J 27 , Lundvall L 47 , Massuger LF 63 , Matsuo K 49 , McGuire V 64 , McLaughlin JR 65 , McNeish I 66 , Menon U 41 , Milne RL 10 , Modugno F 67 , Moysich KB 57 , Ness RB 68 , Nevanlinna H 58 , Eilber U 23 , Odunsi K 69 , Olson SH 70 , Orlow I 70 , Orsulic S 51 , Weber RP 71 , Paul J 43 , Pearce CL 72 , Pejovic T 12 , Pelttari LM 58 , Pike MC 73 , Poole EM 74 , Risch HA 75 , Rosen B 76 , Rossing MA 77 , Rothstein JH 78 , Rudolph A 23 , Runnebaum IB 33 , Rzepecka IK 28 , Salvesen HB 15 , Schernhammer E 74 , Schwaab I 79 , Shu XO 80 , Shvetsov YB 81 , Siddiqui N 82 , Sieh W 78 , Song H 3 , Southey MC 83 , Spiewankiewicz B 84 , Sucheston L 57 , Teo SH 85 , Terry KL 25 , Thompson PJ 44 , Thomsen L 86 , Tangen IL 15 , Tworoger SS 87 , van Altena AM 63 , Vierkant RA 88 , Vergote I 30 , Walsh CS 51 , Wang-Gohrke S 23 , Wentzensen N 17 , Whittemore AS 78 , Wicklund KG 77 , Wilkens LR 81 , Wu AH 4 , Wu X 46 , Woo YL 60 , Yang H 17 , Zheng W 89 , Ziogas A 8 , Hasmad HN 90 , Berchuck A 91 , Georgia Chenevix-Trench , AOCS management group , Iversen ES 92 , Schildkraut JM 93 , Ramus SJ 4 , Goode EL 94 , Monteiro AN 1 , Gayther SA 4 , Narod SA 95 , Pharoah PD 96 , Sellers TA 1 , Phelan CM 1

Affiliations 

  • 1 Division of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America
  • 2 Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, United States of America
  • 3 Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
  • 4 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, United States of America
  • 5 Division of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America; Clinical and Translational Research Organization, All Children's Hospital Johns Hopkins Medicine, St Petersburg, Florida, United States of America
  • 6 Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida, United States of America
  • 7 Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands; Comprehensive Cancer Center The Netherlands, Nijmegen, The Netherlands
  • 8 Genetic Epidemiology Research Institute, Center for Cancer Genetics Research and Prevention, University of California Irvine, Irvine, California, United States of America
  • 9 N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus
  • 10 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
  • 11 Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America
  • 12 Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, Oregon, United States of America; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
  • 13 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Erlangen, Germany
  • 14 Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
  • 15 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway
  • 16 Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany
  • 17 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America
  • 18 Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, Canada
  • 19 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America
  • 20 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland; Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
  • 21 Cancer Genetics Laboratory Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Australia; Department of Pathology, the University of Melbourne, Parkville, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
  • 22 Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, United Kingdom; The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
  • 23 German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
  • 24 Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, United States of America
  • 25 Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
  • 26 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America
  • 27 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 28 Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 29 Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen, Germany; Department of Gynaecology and Gynaecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
  • 30 Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
  • 31 Department of Epidemiology, The Geisel School of Medicine Hanover, New Hampshire, United States of America; Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States of America
  • 32 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 33 Department of Gynecology, Jena University Hospital, Friedrich Schiller University, Jena, Germany
  • 34 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom; Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, United States of America
  • 35 Faculty of Medicine, University of Southampton, Southampton, United Kingdom
  • 36 Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
  • 37 Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany
  • 38 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Erlangen, Germany; University of California at Los Angeles, David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, Los Angeles, California, United States of America
  • 39 Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas, United States of America
  • 40 Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
  • 41 Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom
  • 42 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia; Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia
  • 43 The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
  • 44 Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America; Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
  • 45 Department of Oncology, The Centre for Cancer Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom
  • 46 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
  • 47 The Juliane Marie Centre, Department of Gynecology, Righospitalet, University of Copenhagen, Copenhagen, Denmark
  • 48 Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 49 Department of Preventive Medicine, Kyushu University Faculty of Medical Science, Nagoya, Aichi, Japan
  • 50 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 51 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
  • 52 Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America
  • 53 Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
  • 54 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 55 Vesalius Research Center, VIB, Leuven, Belgium; Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Belgium
  • 56 Cancer Control Research, BC Cancer Agency, Vancouver, Canada
  • 57 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, United States of America
  • 58 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland
  • 59 College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, United States of America
  • 60 Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
  • 61 Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 62 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
  • 63 Department of Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
  • 64 Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, California, United States of America
  • 65 Public Health Ontario, Toronto, Canada
  • 66 Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer research Centre, Beatson Institute for Cancer Research, Glasgow, UK
  • 67 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America; Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
  • 68 The University of Texas School of Public Health, Houston, Texas, United States of America
  • 69 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America
  • 70 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
  • 71 Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, United States of America
  • 72 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, United States of America; Department of Epidemiology, University of Michigan School of Public Health,Ann Arbor, Michigan, United States of America
  • 73 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, United States of America; Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
  • 74 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
  • 75 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, United States of America
  • 76 Department of Gynecology-Oncology, Princess Margaret Hospital, and Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 77 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States of America
  • 78 Department of Health Research and Policy- Epidemiology, Stanford University School of Medicine, Stanford, California, United States of America
  • 79 Institut für Humangenetik, Wiesbaden, Germany
  • 80 Epidemiology Center and Vanderbilt, Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
  • 81 Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, United States of America
  • 82 Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, United Kingdom
  • 83 Department of Pathology, the University of Melbourne, Parkville, Australia
  • 84 Department of Gynecologic Oncology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 85 Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia; University Malaya Cancer Research Institute, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Maylaysia
  • 86 Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 87 Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
  • 88 Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America
  • 89 Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
  • 90 Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia
  • 91 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, United States of America
  • 92 Department of Statistics, Duke University, Durham, North Carolina, United States of America
  • 93 Cancer Prevention, Detection & Control Research Program, Duke Cancer Institute, Durham, North Carolina, United States of America
  • 94 Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, United States of America
  • 95 Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada
  • 96 Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
PLoS One, 2015;10(6):e0128106.
PMID: 26091520 DOI: 10.1371/journal.pone.0128106

Abstract

BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.

METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.

RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).

CONCLUSION: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

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

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