Journal of the National Cancer Institute

, volume 112 , issue 10 , pages 1003-1012

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

Jun Zhong ¹

Ashley Jermusyk ¹

Lang Wu ²

Jason D. Hoskins ¹

Irene Collins ¹

Evelina Mocci ³

Mingfeng Zhang ^{1, 4}

Lei Song ⁵

Charles C. Chung ⁵

Tongwu Zhang ⁵

Wenming Xiao ^{6, 7}

Demetrius Albanes ⁵

Gabriella Andreotti ⁵

Alan A. Arslan ^{8, 9, 10}

A. Babic ¹¹

William R. Bamlet ¹²

Laura Beane-Freeman ⁵

Sonja Berndt ⁵

Ayelet Borgida ¹³

P M Bracci ¹⁴

Lauren Brais ¹¹

Paul Brennan ¹⁵

Bas Bueno-De-Mesquita ^{16, 17, 18, 19}

J E Buring ^{20, 21}

Federico Canzian ²²

Erica J. Childs ³

Michelle Cotterchio ^{23, 24}

Mengmeng Du ²⁵

Charlie S. Fuchs ²⁶

Steven Gallinger ¹³

J. Michael Gaziano ^{20, 27, 28}

G. R. Giles ^{29, 30, 31}

EDWARD GIOVANNUCCI ¹¹

M. G. Goggins ³²

Gary E. Goodman ³³

Phyllis J. Goodman ³⁴

Christopher Haiman ³⁵

Patricia Hartge ⁵

Manal Hasan ³⁶

K Helzlsouer ³⁷

Elizabeth A. Holly ³⁸

Eric E. Klein ³⁹

Manolis Kogevinas ^{40, 41, 42, 43}

Robert J. Kurtz ⁴⁴

Loïc Le Marchand ⁴⁵

Nuria Malats ⁴⁶

Satu Männistö ⁴⁷

R W Milne ^{29, 30, 48}

Rachel Neale ⁴⁹

K.H. Ng ¹¹

O Obazee ²²

Ann L Oberg ¹²

I Orlow ²⁵

Alpa Patel ⁵⁰

Ulrike Peters ³³

Miquel Porta ^{41, 42}

Nathaniel Rothman ⁵

Ghislaine Scelo ^{15, 29, 30}

HOWARD D. SESSO ^{20, 21}

Gianluca Severi ⁵¹

Sabina Sieri ⁵²

Debra Silverman ⁵

M Sund ⁵³

Anne Tjønneland ^{54, 55, 56}

Mark D Thornquist ³³

Geoffrey Tobias ⁵

Stephen K. Van Den Eeden ⁵⁷

Kala Visvanathan ⁵⁸

Jean Wactawski-Wende ⁵⁹

Nicolas Wentzensen ⁵

Emily White ^{33, 60}

Herbert Yu ⁴⁵

陈元 Yuan Chen ¹¹

Anne Zeleniuch-Jacquotte ^{9, 61}

ROBERT HOOVER ⁵

Kevin Brown ¹

Charles Kooperberg ³³

Harvey Risch ⁶²

E J Jacobs ⁶³

Donghui Li ⁶⁴

Herbert Yu ⁵

蔡辉 Cai Hui ²

STEPHEN CHANOCK ⁵

Brian M Wolpin ¹¹

Rachael Z. Stolzenberg-Solomon ⁵

Nilanjan Chatterjee ^{5, 65}

Alison Klein ^{3, 32}

Jill Palmer Smith ⁶⁶

Peter Kraft ^{21, 67}

Jianxin Shi ⁵

Gloria M. Petersen ¹²

Wei Zheng ²

Laufey Amundadottir ¹

Hide authors affiliations Show authors affiliations: 67 affiliations

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

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

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

Yale Cancer Center, New Haven, CT, USA |

²⁷

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

²⁸

Boston VA Healthcare System, Boston, MA, USA |

²⁹

Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia |

³⁰

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

³¹

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

³²

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

³³

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

³⁴

SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA |

³⁵

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

³⁶

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

³⁷

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

³⁸

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

³⁹

Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA |

⁴⁰

ISGLOBAL, Centre for Research in Environmental Epidemiology, Barcelona, Spain |

⁴¹

Ciber Epidemiología y Salud Pública, Barcelona, Spain |

⁴²

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

Autonomous University of Barcelona

Hospital del Mar Research Institute

⁴³

Universitat Pompeu Fabra, Barcelona, Spain |

⁴⁴

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

⁴⁵

Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA |

⁴⁶

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

⁴⁷

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

⁴⁸

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

Monash University

Monash Health

⁴⁹

Population health department, QIMR Berghofer Medical Research Institute, Brisbane, Australia |

⁵⁰

Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA |

⁵¹

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

University of Versailles Saint-Quentin-en-Yvelines

Université Paris-Saclay

French Institute of Health and Medical Research

Institut Gustave Roussy

⁵²

Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy |

⁵³

Department of Surgical and Perioperative Sciences, Umeå university, Umeå, Sweden |

⁵⁴

Danish Cancer Society Research Center, Copenhagen, Denmark |

⁵⁵

Department of Public health, University of Copenhagen, Copenhagen, Denmark |

⁵⁶

Hellenic Health Foundation, Athens, Greece |

⁵⁷

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA |

⁵⁸

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

⁵⁹

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

⁶⁰

Department of Epidemiology, University of Washington, Seattle, WA, USA |

⁶¹

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

⁶²

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

⁶³

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

⁶⁴

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

⁶⁵

Department of Biostatistics, Bloomberg School of Public Health, Baltimore, MD, USA |

⁶⁶

Department of Medicine, Georgetown University, Washington, DC, USA |

⁶⁷

Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA |

Publication type: Journal Article

Publication date: 2020-04-05

Oxford University Press

Journal of the National Cancer Institute

scimago Q1

wos Q1

SJR: 5.703

CiteScore: 17.4

Impact factor: 7.2

ISSN: 00278874, 14602105

DOI: 10.1093/jnci/djz246

Copy DOI

PubMed ID: 31917448

Cancer Research

Oncology

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.

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Zhong J. et al. A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer // Journal of the National Cancer Institute. 2020. Vol. 112. No. 10. pp. 1003-1012.

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@article{2020_Zhong,

author = {Jun Zhong and Ashley Jermusyk and Lang Wu and Jason D. Hoskins and Irene Collins and Evelina Mocci and Mingfeng Zhang and Lei Song and Charles C. Chung and Tongwu Zhang and Wenming Xiao and Demetrius Albanes and Gabriella Andreotti and Alan A. Arslan and A. Babic and William R. Bamlet and Laura Beane-Freeman and Sonja Berndt and Ayelet Borgida and P M Bracci and Lauren Brais and Paul Brennan and Bas Bueno-De-Mesquita and J E Buring and Federico Canzian and Erica J. Childs and Michelle Cotterchio and Mengmeng Du and Charlie S. Fuchs and Steven Gallinger and J. Michael Gaziano and G. R. Giles and EDWARD GIOVANNUCCI and M. G. Goggins and Gary E. Goodman and Phyllis J. Goodman and Christopher Haiman and Patricia Hartge and Manal Hasan and K Helzlsouer and Elizabeth A. Holly and Eric E. Klein and Manolis Kogevinas and Robert J. Kurtz and Loïc Le Marchand and Nuria Malats and Satu Männistö and R W Milne and Rachel Neale and K.H. Ng and others},

title = {A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer},

journal = {Journal of the National Cancer Institute},

year = {2020},

volume = {112},

publisher = {Oxford University Press},

month = {apr},

url = {https://doi.org/10.1093/jnci/djz246},

number = {10},

pages = {1003--1012},

doi = {10.1093/jnci/djz246}

}

MLA

Cite this

MLA Copy

Zhong, Jun, et al. “A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.” Journal of the National Cancer Institute, vol. 112, no. 10, Apr. 2020, pp. 1003-1012. https://doi.org/10.1093/jnci/djz246.

Publisher

Oxford University Press

Journal

Journal of the National Cancer Institute

scimago Q1

wos Q1

SJR

5.703

CiteScore

17.4

Impact factor

7.2

ISSN

00278874 (Print)

14602105 (Electronic)