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Cancer Res. 2016 Sep 1;76(17):5103-14. doi: 10.1158/0008-5472.CAN-15-2980. Epub 2016 Apr 20.

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

Fehringer G1, Kraft P2, Pharoah PD3, Eeles RA4, Chatterjee N5, Schumacher FR6, Schildkraut JM7, Lindström S2, Brennan P8, Bickeböller H9, Houlston RS4, Landi MT5, Caporaso N5, Risch A10, Amin Al Olama A11, Berndt SI5, Giovannucci EL2, Grönberg H12, Kote-Jarai Z4, Ma J13, Muir K14, Stampfer MJ15, Stevens VL16, Wiklund F12, Willett WC2, Goode EL17, Permuth JB18, Risch HA19, Reid BM18, Bezieau S20, Brenner H21, Chan AT22, Chang-Claude J23, Hudson TJ24, Kocarnik JK25, Newcomb PA25, Schoen RE26, Slattery ML27, White E25, Adank MA28, Ahsan H29, Aittomäki K30, Baglietto L31, Blomquist C30, Canzian F32, Czene K12, Dos-Santos-Silva I33, Eliassen AH34, Figueroa JD5, Flesch-Janys D35, Fletcher O36, Garcia-Closas M5, Gaudet MM16, Johnson N36, Hall P12, Hazra A15, Hein R37, Hofman A38, Hopper JL39, Irwanto A40, Johansson M41, Kaaks R23, Kibriya MG29, Lichtner P42, Liu J40, Lund E43, Makalic E39, Meindl A44, Müller-Myhsok B45, Muranen TA30, Nevanlinna H30, Peeters PH46, Peto J33, Prentice RL25, Rahman N47, Sanchez MJ48, Schmidt DF39, Schmutzler RK49, Southey MC31, Tamimi R15, Travis RC50, Turnbull C47, Uitterlinden AG51, Wang Z5, Whittemore AS52, Yang XR5, Zheng W53, Buchanan DD31, Casey G6, Conti DV6, Edlund CK6, Gallinger S1, Haile RW52, Jenkins M31, Le Marchand L54, Li L55, Lindor NM56, Schmit SL6, Thibodeau SN17, Woods MO57, Rafnar T58, Gudmundsson J58, Stacey SN58, Stefansson K58, Sulem P58, Chen YA18, Tyrer JP3, Christiani DC2, Wei Y2, Shen H59, Hu Z59, Shu XO53, Shiraishi K60, Takahashi A61, Bossé Y62, Obeidat M63, Nickle D64, Timens W65, Freedman ML66, Li Q67, Seminara D5, Chanock SJ5, Gong J25, Peters U25, Gruber SB6, Amos CI68, Sellers TA18, Easton DF3, Hunter DJ2, Haiman CA6, Henderson BE6, Hung RJ69; Ovarian Cancer Association Consortium (OCAC); PRACTICAL Consortium; Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON); Colorectal Transdisciplinary (CORECT) Study; African American Breast Cancer Consortium (AABC) and African Ancestry Prostate Cancer Consortium (AAPC).

Author information

1
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
2
Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
3
University of Cambridge, Cambridge, United Kingdom.
4
Institute of Cancer Research, London, United Kingdom.
5
National Cancer Instititute, Bethesda, Maryland.
6
University of Southern California, Los Angeles, California.
7
University of Virginia, Charlottesville, Virginia.
8
International Agency for Research on Cancer, Lyon, France.
9
University of Göttingen, Medical School, Göttingen, Germany.
10
Division of Cancer Genetics/Epigenetics, Department of Molecular Biology, University of Salzburg, Salzburg, Austria. Division of Epigenomics and Cancer Risk Factors, DKFZ - German Cancer Research Center, Heidelberg, Germany. Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany.
11
Cambridge University, Cambridge, United Kingdom.
12
Karolinska Institutet, Stockholm, Sweden.
13
Harvard Medical School, Boston Massachusetts. Brigham and Women's Hospital, Boston, Massachusetts.
14
University of Manchester, Manchester, United Kingdom. The University of Warwick, Coventry, United Kingdom.
15
Harvard Medical School, Boston Massachusetts.
16
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
17
Mayo Clinic, Rochester, Minnesota.
18
Moffitt Cancer Center, Tampa, Florida.
19
Yale School of Public Health, New Haven, Connecticut.
20
Service de Génétique Médicale, Nantes, France.
21
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
22
Massachusetts General Hospital, Boston, Massachusetts.
23
National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany.
24
Ontario Institute for Cancer Research, Toronto, Ontario.
25
Fred Hutchinson Cancer Research Center, Seattle, Washington.
26
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
27
University of Utah Health Sciences Center, Salt Lake City, Utah.
28
VU University Medical Center, Amsterdam, the Netherlands.
29
University of Chicago, Chicago, Illinois.
30
University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
31
The University of Melbourne, Melbourne, Victoria, Australia.
32
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
33
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
34
Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Harvard Medical School, Boston Massachusetts.
35
University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
36
Breakthrough Research Centre, The Institute of Cancer Research, London, United Kingdom.
37
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany. Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany.
38
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
39
Melbourne School of Population Health, University of Melbourne, Melbourne, Victoria, Australia.
40
Genome Institute of Singapore, Singapore.
41
International Agency for Research on Cancer, Lyon, France. Department of Biobank Research, Umea University, Umea, Sweden.
42
German Research Center for Environmental Health, Neuherberg, Germany.
43
Institute of Community Medicine, UiT The Arctic University of Norway, Tromso, Norway.
44
Technische Universität München, Munich, Germany.
45
Max Planck Institute of Psychiatry, Munich, Germany.
46
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands.
47
Institute of Cancer Research, Sutton, United Kingdom.
48
Escuela Andaluza de Salud Publica, Instituto de Investigacion Biosanitaria ibs. GRANADA, Granada, Spain. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain. CIBER de Epidemiología y Salud Pública CIBERESP, Madrid, Spain.
49
University of Cologne, Cologne, Germany.
50
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
51
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
52
Stanford University, Stanford, California.
53
Vanderbilt University, Nashville, Tennessee.
54
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
55
Case Comprehensive Cancer Center and Mary Ann Swetland Center for Environmental Health, Case Western Reserve University, Cleveland, Ohio.
56
Mayo Clinic, Scottsdale, Arizona.
57
Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
58
deCODE genetics, Amgen, Reykjavik, Iceland.
59
Nanjing Medical University School of Public Health, Nanjing, China.
60
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
61
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
62
Department of Molecular Medicine, Institut universitaire de cardiologie et de pneumologie de Québec, Laval University, Québec, Canada.
63
University of British Columbia Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.
64
Merck & Co, Merck Research Laboratories, Seattle, Washington.
65
University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, the Netherlands.
66
Dana-Farber Cancer Institute, Boston, Massachusetts.
67
Xiamen University, Xiamen, China.
68
Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
69
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada. rayjean.hung@lunenfeld.ca.

Abstract

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14.

PMID:
27197191
PMCID:
PMC5010493
[Available on 2017-03-01]
DOI:
10.1158/0008-5472.CAN-15-2980
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

of Potential Conflicts of Interest: Dr. David Nickle is a full time employee at Merck & Co. No potential conflicts of interest were disclosed by other authors.

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