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PLoS One. 2015 Jun 19;10(6):e0128106. doi: 10.1371/journal.pone.0128106. eCollection 2015.

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

Chornokur G1, Lin HY2, Tyrer JP3, Lawrenson K4, Dennis J3, Amankwah EK5, Qu X2, Tsai YY1, Jim HS6, Chen Z2, Chen AY2, Permuth-Wey J1, Aben KK7, Anton-Culver H8, Antonenkova N9, Bruinsma F10, Bandera EV11, Bean YT12, Beckmann MW13, Bisogna M14, Bjorge L15, Bogdanova N16, Brinton LA17, Brooks-Wilson A18, Bunker CH19, Butzow R20, Campbell IG21, Carty K22, Chang-Claude J23, Cook LS24, Cramer DW25, Cunningham JM26, Cybulski C27, Dansonka-Mieszkowska A28, du Bois A29, Despierre E30, Dicks E3, Doherty JA31, Dörk T32, Dürst M33, Easton DF34, Eccles DM35, Edwards RP36, Ekici AB37, Fasching PA38, Fridley BL39, Gao YT40, Gentry-Maharaj A41, Giles GG42, Glasspool R43, Goodman MT44, Gronwald J27, Harrington P45, Harter P29, Hein A13, Heitz F29, Hildebrandt MA46, Hillemanns P32, Hogdall CK47, Hogdall E48, Hosono S49, Jakubowska A27, Jensen A50, Ji BT17, Karlan BY51, Kelemen LE52, Kellar M12, Kiemeney LA53, Krakstad C15, Kjaer SK54, Kupryjanczyk J28, Lambrechts D55, Lambrechts S30, Le ND56, Lee AW4, Lele S57, Leminen A58, Lester J51, Levine DA14, Liang D59, Lim BK60, Lissowska J61, Lu K62, Lubinski J27, Lundvall L47, Massuger LF63, Matsuo K49, McGuire V64, McLaughlin JR65, McNeish I66, Menon U41, Milne RL10, Modugno F67, Moysich KB57, Ness RB68, Nevanlinna H58, Eilber U23, Odunsi K69, Olson SH70, Orlow I70, Orsulic S51, Weber RP71, Paul J43, Pearce CL72, Pejovic T12, Pelttari LM58, Pike MC73, Poole EM74, Risch HA75, Rosen B76, Rossing MA77, Rothstein JH78, Rudolph A23, Runnebaum IB33, Rzepecka IK28, Salvesen HB15, Schernhammer E74, Schwaab I79, Shu XO80, Shvetsov YB81, Siddiqui N82, Sieh W78, Song H3, Southey MC83, Spiewankiewicz B84, Sucheston L57, Teo SH85, Terry KL25, Thompson PJ44, Thomsen L86, Tangen IL15, Tworoger SS87, van Altena AM63, Vierkant RA88, Vergote I30, Walsh CS51, Wang-Gohrke S23, Wentzensen N17, Whittemore AS78, Wicklund KG77, Wilkens LR81, Wu AH4, Wu X46, Woo YL60, Yang H17, Zheng W89, Ziogas A8, Hasmad HN90, Berchuck A91; Georgia Chenevix-Trench; AOCS management group, Iversen ES92, Schildkraut JM93, Ramus SJ4, Goode EL94, Monteiro AN1, Gayther SA4, Narod SA95, Pharoah PD96, Sellers TA1, Phelan CM1.

Author information

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.

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.

PMID:
26091520
PMCID:
PMC4474865
DOI:
10.1371/journal.pone.0128106
[Indexed for MEDLINE]
Free PMC Article

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