Format

Send to

Choose Destination
Nat Commun. 2018 Aug 9;9(1):3166. doi: 10.1038/s41467-018-05427-7.

Identification of nine new susceptibility loci for endometrial cancer.

O'Mara TA1, Glubb DM2, Amant F3, Annibali D3, Ashton K4,5,6, Attia J4,7, Auer PL8,9, Beckmann MW10, Black A11, Bolla MK12, Brauch H13,14,15, Brenner H15,16,17, Brinton L11, Buchanan DD18,19,20,21, Burwinkel B22,23, Chang-Claude J24,25, Chanock SJ11, Chen C26, Chen MM27, Cheng THT28, Clarke CL29, Clendenning M18,21, Cook LS30,31, Couch FJ32, Cox A33, Crous-Bous M27,34, Czene K35, Day F36, Dennis J12, Depreeuw J3,37,38, Doherty JA39, Dörk T40, Dowdy SC41, Dürst M42, Ekici AB43, Fasching PA10,44, Fridley BL45, Friedenreich CM31, Fritschi L46, Fung J47, García-Closas M11,48, Gaudet MM49, Giles GG19,50,51, Goode EL52, Gorman M28, Haiman CA53, Hall P35,54, Hankison SE34,55, Healey CS56, Hein A10, Hillemanns P40, Hodgson S57, Hoivik EA58,59, Holliday EG4,7, Hopper JL19, Hunter DJ27,60, Jones A28, Krakstad C58,59, Kristensen VN61,62,63, Lambrechts D38,64, Marchand LL65, Liang X66, Lindblom A67, Lissowska J68, Long J69, Lu L70, Magliocco AM71, Martin L72, McEvoy M7, Meindl A73, Michailidou K12,74, Milne RL19,50, Mints M75, Montgomery GW2,47, Nassir R76, Olsson H77, Orlow I66, Otton G78, Palles C28, Perry JRB36, Peto J79, Pooler L53, Prescott J34, Proietto T78, Rebbeck TR80,81, Risch HA70, Rogers PAW82, Rübner M83, Runnebaum I42, Sacerdote C84,85, Sarto GE86, Schumacher F87, Scott RJ4,5,6,88, Setiawan VW53, Shah M56, Sheng X53, Shu XO69, Southey MC18,89, Swerdlow AJ90,91, Tham E67,92, Trovik J58,59, Turman C27, Tyrer JP56, Vachon C93, VanDen Berg D53, Vanderstichele A94, Wang Z11, Webb PM95, Wentzensen N11, Werner HMJ58,59, Winham SJ96, Wolk A97, Xia L53, Xiang YB98, Yang HP11, Yu H65, Zheng W69, Pharoah PDP12,56, Dunning AM56, Kraft P27,60, De Vivo I27,34, Tomlinson I28,72, Easton DF12,56, Spurdle AB99, Thompson DJ100.

Author information

1
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, 4006, QLD, Australia. Tracy.OMara@qimrberghofer.edu.au.
2
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, 4006, QLD, Australia.
3
Department of Obstetrics and Gynecology, University Hospitals KU Leuven, University of Leuven, Division of Gynecologic Oncology, Leuven, 3000, Belgium.
4
John Hunter Hospital, Hunter Medical Research Institute, Newcastle, 2305, NSW, Australia.
5
University of Newcastle, Centre for Information Based Medicine, Callaghan, 2308, NSW, Australia.
6
University of Newcastle, Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, Callaghan, 2308, NSW, Australia.
7
University of Newcastle, Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, Callaghan, 2308, NSW, Australia.
8
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, 98109, WA, USA.
9
University of Wisconsin-Milwaukee, Zilber School of Public Health, Milwaukee, 53205, WI, USA.
10
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, 91054, Germany.
11
National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, 20892, MD, USA.
12
Department of Public Health and Primary Care, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, CB1 8RN, UK.
13
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, 70376, Germany.
14
University of Tübingen, Tübingen, 72074, Germany.
15
German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, 69120, Germany.
16
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
17
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, 69120, Germany.
18
Department of Clinical Pathology, The University of Melbourne, Melbourne, 3010, VIC, Australia.
19
The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, 3010, VIC, Australia.
20
Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, 3010, VIC, Australia.
21
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, 3010, VIC, Australia.
22
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, 69120, Germany.
23
Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
24
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
25
University Medical Center Hamburg-Eppendorf, Cancer Epidemiology, University Cancer Center Hamburg (UCCH), Hamburg, 20246, Germany.
26
Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, 98109, WA, USA.
27
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA.
28
University of Oxford, Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, Oxford, OX3 7BN, UK.
29
University of Sydney, Westmead Institute for Medical Research, Sydney, 2145, NSW, Australia.
30
University of New Mexico, University of New Mexico Health Sciences Center, Albuquerque, 87131, NM, USA.
31
Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, T2N 4N2, AB, Canada.
32
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905, MN, USA.
33
Department of Oncology and Metabolism, University of Sheffield, Sheffield Institute for Nucleic Acids (SInFoNiA), Sheffield, S10 2TN, UK.
34
Department of Medicine, Harvard Medical School, Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, 02115, MA, USA.
35
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 171 65, Sweden.
36
University of Cambridge, MRC Epidemiology Unit, School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
37
VIB, Vesalius Research Center, Leuven, 3000, Belgium.
38
Department of Human Genetics, University of Leuven, Laboratory for Translational Genetics, Leuven, 3000, Belgium.
39
Cancer Research Huntsman Cancer Institute Department of Population Health Sciences, University of Utah, Salt Lake City, 84112, UT, USA.
40
Gynaecology Research Unit, Hannover Medical School, Hannover, 30625, Germany.
41
Department of Obstetrics and Gynecology, Mayo Clinic, Division of Gynecologic Oncology, Rochester, 55905, MN, USA.
42
Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, 07743, Germany.
43
Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Institute of Human Genetics, University Hospital Erlangen, Erlangen, 91054, Germany.
44
Department of Medicine, University of California at Los Angeles, David Geffen School of Medicine, Division of Hematology and Oncology, Los Angeles, 90095, CA, USA.
45
Department of Biostatistics, Kansas University Medical Center, Kansas City, 66160, KS, USA.
46
Curtin University, School of Public Health, Perth, 6102, WA, Australia.
47
University of Queensland, Institute for Molecular Bioscience, Brisbane, 4072, QLD, Australia.
48
Institute of Cancer Research, Division of Genetics and Epidemiology, London, SM2 5NG, UK.
49
American Cancer Society, Epidemiology Research Program, Atlanta, 30303, GA, USA.
50
Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, 3004, VIC, Australia.
51
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, 3004, VIC, Australia.
52
Department of Health Science Research, Mayo Clinic, Division of Epidemiology, Rochester, 55905, MN, USA.
53
Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, 90033, CA, USA.
54
Department of Oncology, South General Hospital, Stockholm, 118 83, Sweden.
55
Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, Amherst, 01003, MA, USA.
56
Department of Oncology, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, CB1 8RN, UK.
57
Department of Clinical Genetics, St George's, University of London, London, SW17 0RE, UK.
58
Department of Clinical Science, University of Bergen, Centre for Cancer Biomarkers, Bergen, 5020, Norway.
59
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, 5021, Norway.
60
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA.
61
Department of Cancer Genetics, Oslo University Hospital, Radiumhospitalet, Institute for Cancer Research, Oslo, 0379, Norway.
62
University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, 0450, Norway.
63
Department of Clinical Molecular Biology, University of Oslo, Oslo University Hospital, Oslo, 0450, Norway.
64
VIB, VIB Center for Cancer Biology, Leuven, 3001, Belgium.
65
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, 96813, HI, USA.
66
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, 10065, NY, USA.
67
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, 171 76, Sweden.
68
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center-Oncology Institute, Warsaw, 02-034, Poland.
69
Department of Medicine, Vanderbilt University School of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Nashville, 37232, TN, USA.
70
Chronic Disease Epidemiology, Yale School of Public Health, New Haven, 06510, CT, USA.
71
Department of Anatomic Pathology, Moffitt Cancer Center and Research Institute, Tampa, 33612, FL, USA.
72
University of Birmingham, Institute of Cancer and Genomic Sciences, Birmingham, B15 2TT, UK.
73
Department of Gynecology and Obstetrics, Ludwig-Maximilians University of Munich, Munich, 80336, Germany.
74
Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
75
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, 171 76, Sweden.
76
Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, 95817, CA, USA.
77
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, 222 42, Sweden.
78
University of Newcastle, School of Medicine and Public Health, Callaghan, 2308, NSW, Australia.
79
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
80
Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA.
81
Dana-Farber Cancer Institute, Boston, 02115, MA, USA.
82
Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women's Hospital, Gynaecology Research Centre, Parkville, 3052, VIC, Australia.
83
Department of Gynaecology and Obstetrics, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Erlangen, 91054, Germany.
84
Center for Cancer Prevention (CPO-Peimonte), Turin, 10126, Italy.
85
Human Genetics Foundation (HuGeF), Turino, 10126, Italy.
86
Department of Obstetrics and Gynecology, University of Wisconsin, School of Medicine and Public Health, Madison, 53715, WI, USA.
87
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, 44106, OH, USA.
88
John Hunter Hospital, Division of Molecular Medicine, Pathology North, Newcastle, 2308, NSW, Australia.
89
Monash University, Precision Medicine, School of Clinical Sciences at Monash Health, Clayton, 3168, VIC, Australia.
90
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG, UK.
91
Division of Breast Cancer Research, The Institute of Cancer Research, London, SW7 3RP, UK.
92
Karolinska Institutet, Clinical Genetics, Stockholm, 171 76, Sweden.
93
Department of Health Sciences Research, Mayo Clinic, Rochester, 55905, MN, USA.
94
Department of Obstetrics and Gynaecology, University Hospitals Leuven, Division of Gynecologic Oncology, Leuven Cancer Institute, Leuven, 3000, Belgium.
95
Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, 4006, QLD, Australia.
96
Department of Health Science Research, Mayo Clinic, Division of Biomedical Statistics and Informatics, Rochester, 55905, MN, USA.
97
Department of Environmental Medicine, Karolinska Institutet, Division of Nutritional Epidemiology, Stockholm, 171 77, Sweden.
98
Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, State Key Laboratory of Oncogene and Related Genes, Shanghai, China.
99
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, 4006, QLD, Australia. Amanda.Spurdle@qimrberghofer.edu.au.
100
Department of Public Health and Primary Care, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, CB1 8RN, UK. djt25@medschl.cam.ac.uk.

Abstract

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Publication type, Grant support

Publication type

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center