A Transcriptome-Wide Association Study (TWAS) Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.,Journal of the National Cancer Institute

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A Transcriptome-Wide Association Study (TWAS) Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.
Journal of the National Cancer Institute ( IF 9.9 ) Pub Date : 2020-01-09 , DOI: 10.1093/jnci/djz246
Jun Zhong ₁ , Ashley Jermusyk ₁ , Lang Wu ₂ , Jason W 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} , Ana Babic ₁₁ , William R Bamlet ₁₂ , Laura Beane-Freeman ₅ , Sonja Berndt ₅ , Ayelet Borgida ₁₃ , Paige M Bracci ₁₄ , Lauren Brais ₁₁ , Paul Brennan ₁₅ , Bas Bueno-de-Mesquita _{16,

17,

18,

19} , Julie Buring _{20,

21} , Federico Canzian ₂₂ , Erica J Childs ₃ , Michelle Cotterchio _{23,

24} , Mengmeng Du ₂₅ , Eric J Duell ₂₆ , Charles Fuchs ₂₇ , Steven Gallinger ₁₃ , J Michael Gaziano _{20,

28,

29} , Graham G Giles _{30,

31,

32} , Edward Giovannucci ₁₁ , Michael Goggins ₃₃ , Gary E Goodman ₃₄ , Phyllis J Goodman ₃₅ , Christopher Haiman ₃₆ , Patricia Hartge ₅ , Manal Hasan ₃₇ , Kathy J Helzlsouer ₃₈ , Elizabeth A Holly ₃₉ , Eric A Klein ₄₀ , Manolis Kogevinas _{41,

42,

43,

44} , Robert J Kurtz ₄₅ , Loic LeMarchand ₄₆ , Núria Malats ₄₇ , Satu Männistö ₄₈ , Roger Milne _{30,

31,

49} , Rachel E Neale ₅₀ , Kimmie Ng ₁₁ , Ofure Obazee ₂₂ , Ann L Oberg ₁₂ , Irene Orlow ₂₅ , Alpa V Patel ₅₁ , Ulrike Peters ₃₄ , Miquel Porta _{42,

43} , Nathaniel Rothman ₅ , Ghislaine Scelo _{15,

30,

31} , Howard D Sesso _{20,

21} , Gianluca Severi ₅₂ , Sabina Sieri ₅₃ , Debra Silverman ₅ , Malin Sund ₅₄ , Anne Tjønneland _{55,

56,

57} , Mark D Thornquist ₃₄ , Geoffrey S Tobias ₅ , Antonia Trichopoulou , Stephen K Van Den Eeden ₅₈ , Kala Visvanathan ₅₉ , Jean Wactawski-Wende ₆₀ , Nicolas Wentzensen ₅ , Emily White _{34,

61} , Herbert Yu ₄₆ , Chen Yuan ₁₁ , Anne Zeleniuch-Jacquotte _{9,

62} , Robert Hoover ₅ , Kevin Brown ₁ , Charles Kooperberg ₃₄ , Harvey A Risch ₆₃ , Eric J Jacobs ₆₄ , Donghui Li ₆₅ , Kai Yu ₅ , Xiao-Ou Shu ₂ , Stephen J Chanock ₅ , Brian M Wolpin ₁₁ , Rachael Z Stolzenberg-Solomon ₅ , Nilanjan Chatterjee _{5,

66} , Alison P Klein _{3,

33} , Jill P Smith ₆₇ , Peter Kraft _{21,

68} , Jianxin Shi ₅ , Gloria M Petersen ₁₂ , Wei Zheng ₂ , Laufey T Amundadottir ₁

Affiliation

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.
US Food and Drug Administration, Silver Spring, MD, USA.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA.
Division of Molecular Genetics and Pathology, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA.
Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA.
Department of Population Health, New York University School of Medicine, New York, NY, USA.
Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Epidemiology and Biostatistics, University of California, CA, USA.
International Agency for Research on Cancer, Lyon, France.
Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment, BA, Bilthoven, The Netherlands.
Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.
Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada.
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona, Spain.
Yale Cancer Center, New Haven, CT, USA.
Division of Aging, Brigham and Women's Hospital, Boston, MA, USA.
Boston VA Healthcare System, Boston, MA, USA.
Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.
ISGlobal, Centre for Research in Environmental Epidemiology, Barcelona, Spain.
CIBER Epidemiología y Salud Pública, Barcelona, Spain.
Hospital del Mar Institute of Medical Research, Universitat Autònoma de Barcelona, Barcelona, Spain.
Universitat Pompeu Fabra, Barcelona, Spain.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain.
Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC, Australia.
Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, Villejuif, France.
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden.
Danish Cancer Society Research Center, Copenhagen, Denmark.
Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
Hellenic Health Foundation, Athens, Greece.
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA.
Department of Epidemiology, University of Washington, Seattle, WA, USA.
Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Biostatistics, Bloomberg School of Public Health, Baltimore, MD, USA.
Department of Medicine, Georgetown University, Washington, DC, USA.
Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.

BACKGROUND Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) 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 (TWAS) in Europeans using three approaches, FUSION, MetaXcan and SMulTiXcan. We integrated GWAS summary statistics from 9,040 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, LTG (n = 95) and Genotype-Tissue Expression, GTEx v7 (n = 174) datasets), and data from 48 different tissues (GTEx v7, n = 74-421 samples). RESULTS We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (FDR < 0.05), 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 6 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.

中文翻译：

全转录组关联研究 (TWAS) 确定了胰腺癌的新候选易感基因。

背景虽然通过全基因组关联研究（GWAS）在欧洲血统的个体中鉴定出了 20 个胰腺癌易感位点，但其大部分遗传性仍然无法解释，而且相关基因也很大程度上未知。方法为了发现新的胰腺癌风险位点和可能的致病基因，我们使用 FUSION、MetaXcan 和 SMulTiXcan 三种方法在欧洲人中进行了胰腺癌全转录组关联研究 (TWAS)。我们整合了 9,040 例胰腺癌病例和 12,496 例对照的 GWAS 摘要统计数据，以及使用来自组织学正常胰腺组织样本的转录组数据构建的基因表达预测模型（NCI 转化基因组学实验室，LTG (n = 95) 和基因型组织表达，GTEx v7 (n = 174) 数据集)，以及来自 48 个不同组织的数据 (GTEx v7，n = 74-421 个样本)。结果我们确定了 25 个基因，其基因预测表达与胰腺癌风险具有统计学显着相关性（FDR < 0.05），包括 11 个新位点的 14 个候选基因（1p36.12：CELA3B；9q31.1：SMC2、SMC2-AS1；10q23.1）。 31: RP11-80H5.9; 12q13.13: BTBD6; 15q26.1: RCCD1; 17q12:, PNMT, CDK12, PGAP3; 1-888D10 .3；和 19p13.11：PGPEP1）和 6 个已知风险位点的 11（5p15.33：TERT、CLPTM1L、ZDHHC11B；7p14.1：INHBA；9q34.2：ABO；13q12.2：PDX1；13q22.1： KLF5；和 16q23.1：WDR59、CFDP1、BCAR1、TMEM170A)。其中 12 个基因（新风险位点处的 CELA3B、SMC2 和 PNMT，以及已知位点处的 TERT、CLPTM1L、INHBA、ABO、PDX1、KLF5、WDR59、CFDP1 和 BCAR1）的关联在 Bonferroni 校正后仍具有统计学显着性。结论通过整合基因表达和基因型数据，我们确定了新的胰腺癌风险位点和值得进一步研究的候选功能基因。

更新日期：2020-01-09

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