A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer-Reference-Cited by-同舟云学术

A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer

Published:2020-04-05 Issue:10 Volume:112 Page:1003-1012
ISSN:0027-8874
Container-title:JNCI: Journal of the National Cancer Institute
language:en
Short-container-title:

Author:

Zhong Jun¹^ORCID,Jermusyk Ashley¹^ORCID,Wu Lang²,Hoskins Jason W¹^ORCID,Collins Irene¹^ORCID,Mocci Evelina³^ORCID,Zhang Mingfeng¹⁴,Song Lei⁵,Chung Charles C⁵,Zhang Tongwu⁵,Xiao Wenming⁶⁷,Albanes Demetrius⁵^ORCID,Andreotti Gabriella⁵,Arslan Alan A⁸⁹¹⁰,Babic Ana¹¹,Bamlet William R¹²,Beane-Freeman Laura⁵,Berndt Sonja⁵,Borgida Ayelet¹³^ORCID,Bracci Paige M¹⁴,Brais Lauren¹¹,Brennan Paul¹⁵^ORCID,Bueno-de-Mesquita Bas¹⁶¹⁷¹⁸¹⁹^ORCID,Buring Julie²⁰²¹,Canzian Federico²²^ORCID,Childs Erica J³,Cotterchio Michelle²³²⁴,Du Mengmeng²⁵,Duell Eric J²⁶,Fuchs Charles²⁷^ORCID,Gallinger Steven¹³,Gaziano J Michael²⁰²⁸²⁹,Giles Graham G³⁰³¹³²^ORCID,Giovannucci Edward¹¹,Goggins Michael³³^ORCID,Goodman Gary E³⁴,Goodman Phyllis J³⁵,Haiman Christopher³⁶,Hartge Patricia⁵,Hasan Manal³⁷,Helzlsouer Kathy J³⁸,Holly Elizabeth A³⁹,Klein Eric A⁴⁰,Kogevinas Manolis⁴¹⁴²⁴³⁴⁴,Kurtz Robert J⁴⁵,LeMarchand Loic⁴⁶^ORCID,Malats Núria⁴⁷^ORCID,Männistö Satu⁴⁸,Milne Roger³⁰³¹⁴⁹^ORCID,Neale Rachel E⁵⁰^ORCID,Ng Kimmie¹¹,Obazee Ofure²²,Oberg Ann L¹²^ORCID,Orlow Irene²⁵^ORCID,Patel Alpa V⁵¹,Peters Ulrike³⁴,Porta Miquel⁴²⁴³^ORCID,Rothman Nathaniel⁵,Scelo Ghislaine¹⁵³⁰³¹,Sesso Howard D²⁰²¹^ORCID,Severi Gianluca⁵²^ORCID,Sieri Sabina⁵³^ORCID,Silverman Debra⁵,Sund Malin⁵⁴^ORCID,Tjønneland Anne⁵⁵⁵⁶⁵⁷,Thornquist Mark D³⁴,Tobias Geoffrey S⁵,Trichopoulou Antonia^ORCID,Van Den Eeden Stephen K⁵⁸^ORCID,Visvanathan Kala⁵⁹,Wactawski-Wende Jean⁶⁰,Wentzensen Nicolas⁵^ORCID,White Emily³⁴⁶¹,Yu Herbert⁴⁶,Yuan Chen¹¹^ORCID,Zeleniuch-Jacquotte Anne⁹⁶²,Hoover Robert⁵,Brown Kevin¹^ORCID,Kooperberg Charles³⁴,Risch Harvey A⁶³,Jacobs Eric J⁶⁴,Li Donghui⁶⁵^ORCID,Yu Kai⁵,Shu Xiao-Ou²,Chanock Stephen J⁵^ORCID,Wolpin Brian M¹¹,Stolzenberg-Solomon Rachael Z⁵,Chatterjee Nilanjan⁵⁶⁶^ORCID,Klein Alison P³³³,Smith Jill P⁶⁷,Kraft Peter²¹⁶⁸^ORCID,Shi Jianxin⁵,Petersen Gloria M¹²,Zheng Wei²,Amundadottir Laufey T¹^ORCID

Affiliation:

1. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

2. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

3. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

4. US Food and Drug Administration, Silver Spring, MD, USA

5. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

6. National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA

7. Division of Molecular Genetics and Pathology, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA

8. Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA

9. Department of Population Health, New York University School of Medicine, New York, NY, USA

10. Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA

11. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

12. Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA

13. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada

14. Department of Epidemiology and Biostatistics, University of California, CA, USA

15. International Agency for Research on Cancer, Lyon, France

16. Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment, BA, Bilthoven, The Netherlands

17. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands

18. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

19. Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

20. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, USA

21. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

22. Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany

23. Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada

24. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

25. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

26. Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona, Spain

27. Yale Cancer Center, New Haven, CT, USA

28. Division of Aging, Brigham and Women’s Hospital, Boston, MA, USA

29. Boston VA Healthcare System, Boston, MA, USA

30. Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia

31. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia

32. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia

33. Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

34. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

35. SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

36. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

37. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

38. Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

39. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA

40. Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA

41. ISGlobal, Centre for Research in Environmental Epidemiology, Barcelona, Spain

42. CIBER Epidemiología y Salud Pública, Barcelona, Spain

43. Hospital del Mar Institute of Medical Research, Universitat Autònoma de Barcelona, Barcelona, Spain

44. Universitat Pompeu Fabra, Barcelona, Spain

45. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

46. Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

47. Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain

48. Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland

49. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC, Australia

50. Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia

51. Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA

52. Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, Villejuif, France

53. Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

54. Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden

55. Danish Cancer Society Research Center, Copenhagen, Denmark

56. Department of Public Health, University of Copenhagen, Copenhagen, Denmark

57. Hellenic Health Foundation, Athens, Greece

58. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

59. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

60. Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA

61. Department of Epidemiology, University of Washington, Seattle, WA, USA

62. Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA

63. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA

64. Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA

65. Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

66. Department of Biostatistics, Bloomberg School of Public Health, Baltimore, MD, USA

67. Department of Medicine, Georgetown University, Washington, DC, USA

68. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

Abstract

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Funder

Intramural Research Program

IRP

Division of Cancer Epidemiology and Genetics

National Cancer Institute

US National Institutes of Health

NIH

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

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