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Carcinogenesis. 2015 Nov;36(11):1341-53. doi: 10.1093/carcin/bgv138. Epub 2015 Sep 29.

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.

Lawrenson K1, Iversen ES2, Tyrer J3, Weber RP4, Concannon P5, Hazelett DJ6, Li Q7, Marks JR8, Berchuck A9, Lee JM, Aben KK10, Anton-Culver H11, Antonenkova N12; Australian Cancer Study (Ovarian Cancer); Australian Ovarian Cancer Study Group, Bandera EV13, Bean Y14, Beckmann MW15, Bisogna M16, Bjorge L17, Bogdanova N18, Brinton LA19, Brooks-Wilson A20, Bruinsma F21, Butzow R22, Campbell IG23, Carty K24, Chang-Claude J25, Chenevix-Trench G26, Chen A27, Chen Z27, Cook LS28, Cramer DW29, Cunningham JM30, Cybulski C31, Plisiecka-Halasa J32, Dennis J33, Dicks E33, Doherty JA34, Dörk T18, du Bois A35, Eccles D36, Easton DT33, Edwards RP37, Eilber U25, Ekici AB38, Fasching PA39, Fridley BL40, Gao YT41, Gentry-Maharaj A42, Giles GG43, Glasspool R24, Goode EL44, Goodman MT45, Gronwald J31, Harter P46, Hasmad HN47, Hein A15, Heitz F46, Hildebrandt MA48, Hillemanns P49, Hogdall E50, Hogdall C51, Hosono S52, Jakubowska A31, Paul J24, Jensen A53, Karlan BY54, Kjaer SK55, Kelemen LE56, Kellar M14, Kelley JL57, Kiemeney LA58, Krakstad C17, Lambrechts D59, Lambrechts S60, Le ND61, Lee AW, Cannioto R62, Leminen A63, Lester J54, Levine DA16, Liang D64, Lissowska J32, Lu K65, Lubinski J31, Lundvall L51, Massuger LF66, Matsuo K67, McGuire V68, McLaughlin JR69, Nevanlinna H63, McNeish I70, Menon U42, Modugno F71, Moysich KB62, Narod SA72, Nedergaard L73, Ness RB74, Noor Azmi MA75, Odunsi K76, Olson SH77, Orlow I77, Orsulic S54, Pearce CL78, Pejovic T14, Pelttari LM63, Permuth-Wey J79, Phelan CM79, Pike MC80, Poole EM81, Ramus SJ, Risch HA82, Rosen B83, Rossing MA84, Rothstein JH68, Rudolph A25, Runnebaum IB85, Rzepecka IK31, Salvesen HB17, Budzilowska A32, Sellers TA79, Shu XO86, Shvetsov YB87, Siddiqui N88, Sieh W68, Song H3, Southey MC89, Sucheston L64, Tangen IL17, Teo SH90, Terry KL29, Thompson PJ45, Timorek A91, Tworoger SS81, Van Nieuwenhuysen E60, Vergote I60, Vierkant RA44, Wang-Gohrke S92, Walsh C54, Wentzensen N19, Whittemore AS68, Wicklund KG93, Wilkens LR87, Woo YL94, Wu X48, Wu AH, Yang H19, Zheng W86, Ziogas A95, Coetzee GA6, Freedman ML96, Monteiro AN97, Moes-Sosnowska J32, Kupryjanczyk J32, Pharoah PD3, Gayther SA98, Schildkraut JM99.

Author information

1
Present address: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA and.
2
Department of Statistical Science, Duke University, Durham, NC 27708, USA.
3
Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research laboratory, Cambridge CB2 1TN, UK.
4
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC 27710, USA.
5
Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
6
Departments of Urology and Preventive Medicine, Norris Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.
7
Medical School, Xiamen University, Xiamen 361000, China.
8
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
9
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA.
10
Department for Health Evidence, Nijmegen 6500 HB, The Netherlands, Comprehensive Cancer Center, Utrecht 3542 EG, The Netherlands.
11
Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA.
12
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk 223052, Belarus.
13
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
14
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA, Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
15
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany.
16
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
17
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen 5021, Norway, Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, Bergen 5020, Norway.
18
Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany.
19
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20852, USA.
20
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada, Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
21
Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne Victoria 3004, Australia.
22
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029, Finland, Department of Pathology, Helsinki University Central Hospital, Helsinki 00029, Finland.
23
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 8006, Australia, Department of Pathology, University of Melbourne, Parkville, Victoria 3002, Australia, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3002, Australia.
24
Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK.
25
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69009, Germany.
26
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane Queensland 4029, Australia.
27
Department of Biostatistics, Moffitt Cancer Center, Tampa, FL 33612, USA.
28
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA.
29
Harvard School of Public Health, Boston, MA 02115, USA, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
30
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
31
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland.
32
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02-781, Poland.
33
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
34
Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
35
Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA, Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden 65199, Germany.
36
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK.
37
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK, Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15222, USA.
38
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, Germany.
39
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles CA 90095, USA.
40
Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, KS 66160, USA.
41
Shanghai Cancer Institute, Shanghai 200032, China.
42
Department of Women's Cancer, Institute for Women's Health, University College London, London W1T 7DN, UK.
43
Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne Victoria 3004, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria 3010, Australia.
44
Department of Health Science Research, Mayo Clinic, Rochester, MN 55905, USA.
45
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA, Department of Biomedical Sciences, Community and Population Health Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
46
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen 45136, Germany, Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden 65199, Germany.
47
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya 47500, Malaysia.
48
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
49
Departments of Obstetrics and Gynaecology, Hannover Medical School, Hannover 30625, Germany.
50
Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen DK-2100, Denmark, Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen DK-2100, Denmark.
51
Gyn Clinic, Rigshospitalet, University of Copenhagen DK-2100, Denmark.
52
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan.
53
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen DK-2100, Denmark.
54
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
55
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen DK-2100, Denmark, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen DK-2100, Denmark.
56
Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA.
57
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15222, USA.
58
Department for Health Evidence and Department of Urology, Radboud University Medical Centre, Nijmegen 6500 HB, The Netherlands.
59
Vesalius Research Center, VIB, Leuven 3000, Belgium, Laboratory for Translational Genetics, Department of Oncology, University of Leuven 3000, Belgium.
60
Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, 3000, Belgium.
61
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
62
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
63
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029, Finland.
64
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
65
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
66
Department of Gynaecology, Radboud University Medical Centre, Nijmegen 6500 HB, The Netherlands.
67
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka 812-8582, Japan.
68
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
69
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
70
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow G61 1QH, UK.
71
Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15222, USA, Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15222, USA, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15222, USA, Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15222, USA.
72
Women's College Research Institute, Toronto, Ontario M5G 1N8, Canada.
73
Department of Pathology, Rigshospitalet, University of Copenhagen DK-2100, Denmark.
74
The University of Texas School of Public Health, Houston, TX 77225, USA.
75
Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur 50603, Malaysia.
76
Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
77
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
78
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
79
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
80
Department of Statistical Science, Duke University, Durham, NC 27708, USA, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
81
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
82
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06520, USA.
83
Department of Gynecologic-Oncology, Princess Margaret Hospital, and Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1X6, Canada.
84
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Department of Epidemiology, University of Washington, Seattle, WA 98109, USA.
85
Department of Gynecology, Jena University Hospital - Friedrich Schiller University, Jena D-07743, Germany.
86
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
87
Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii 96826, USA.
88
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
89
Department of Pathology, University of Melbourne, Parkville, Victoria 3002, Australia.
90
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA, University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur 50603, Malaysia.
91
Department of Obstetrics, Gynecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw 03-242, Poland.
92
Department of Obstetrics and Gynecology, University of Ulm, Ulm 89075, Germany.
93
Department of Epidemiology, University of Washington, Seattle, WA 98109, USA.
94
Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur 50603, Malaysia, University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur 50603, Malaysia.
95
Comprehensive Cancer Center, Utrecht 3542 EG, The Netherlands.
96
Department of Medical Oncology, 02115, Dana-Farber Cancer Institute, Boston, MA, USA.
97
Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA and.
98
Present address: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
99
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC 27710, USA, Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC 27710, USA, jms2yf@virginia.edu.

Abstract

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

PMID:
26424751
PMCID:
PMC4635670
DOI:
10.1093/carcin/bgv138
[Indexed for MEDLINE]
Free PMC Article

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