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

被引：35

作者：

Liu, Duo ^{[1
,2
]}

Zhou, Dan ^{[3
,4
]}

Sun, Yanfa ^{[2
,5
,6
,7
]}

Zhu, Jingjing ^{[2
]}

Ghoneim, Dalia ^{[2
]}

Wu, Chong ^{[8
]}

Yao, Qizhi ^{[9
,10
]}

Gamazon, Eric R. ^{[3
,4
,11
,12
]}

Cox, Nancy J. ^{[3
,4
]}

Wu, Lang ^{[2
]}

机构：

[1] Harbin Med Univ, Dept Pharm, Canc Hosp, Harbin, Heilongjiang, Peoples R China

[2] Univ Hawaii Manoa, Div Canc Epidemiol, Populat Sci Pacific Program, Univ Hawaii Canc Ctr, Honolulu, HI 96813 USA

[3] Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Nashville, TN USA

[4] Vanderbilt Univ, Med Ctr, Dept Med, Div Genet Med, Nashville, TN USA

[5] Longyan Univ, Coll Life Sci, Longyan, Fujian, Peoples R China

[6] Fujian Prov Key Lab Prevent & Control Anim Infect, Longyan, Fujian, Peoples R China

[7] Longyan Univ, Key Lab Prevent Vet Med & Biotechnol, Fujian Prov Univ, Longyan, Fujian, Peoples R China

[8] Florida State Univ, Dept Stat, Tallahassee, FL 32306 USA

[9] Baylor Coll Med, Michael E DeBakey Dept Surg, Div Surg Oncol, Houston, TX 77030 USA

[10] Michael E DeBakey VA Med Ctr, Ctr Translat Res Inflammatory Dis CTRID, Houston, TX USA

[11] Univ Cambridge, Clare Hall, Cambridge, England

[12] Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England

来源：

CANCER RESEARCH | 2020年 / 80卷 / 20期

关键词：

BREAST-CANCER; EXPRESSION; LOCI; PROGRESSION; CELL;

D O I：

10.1158/0008-5472.CAN-20-1353

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Pancreatic cancer is among the most well-characterized cancer types, yet a large proportion of the heritability of pancreatic cancer risk remains unclear. Here, we performed a large transcriptome-wide association study to systematically investigate associations between genetically predicted gene expression in normal pancreas tissue and pancreatic cancer risk. Using data from 305 subjects of mostly European descent in the Genotype-Tissue Expression Project, we built comprehensive genetic models to predict normal pancreas tissue gene expression, modifying the UTMOST (unified test for molecular signatures). These prediction models were applied to the genetic data of 8,275 pancreatic cancer cases and 6,723 controls of European ancestry. Thirteen genes showed an association of genetically predicted expression with pancreatic cancer risk at an FDR <= 0.05, including seven previously reported genes (INHBA, SMC2, ABO, PDX1, RCCD1, CFDP1, and PGAP3) and six novel genes not yet reported for pancreatic cancer risk [6q27: SFT2D1 OR (95% confidence interval (CI), 1.54 (1.25-1.89); 13q12.13: MTMR6 OR (95% CI), 0.78 (0.70-0.88); 14q24.3: ACOT2 OR (95% CI), 1.35 (1.17-1.56); 17q12: STARD3 OR (95% CI), 6.49 (2.96-14.27); 17q21.1: GSDMB OR (95% CI), 1.94 (1.45-2.58); and 20p13: ADAM33 OR (95% CI): 1.41 (1.20-1.66)]. The associations for 10 of these genes (SFT2D1, MTMR6, ACOT2, STARD3, GSDMB, ADAM33, SMC2, RCCD1, CFDP1, and PGAP3) remained statistically significant even after adjusting for risk SNPs identified in previous genome-wide association study. Collectively, this analysis identified novel candidate susceptibility genes for pancreatic cancer that warrant further investigation. Significance: A transcriptome-wide association analysis identified seven previously reported and six novel candidate susceptibility genes for pancreatic cancer risk.

引用

页码：4346 / 4354

页数：9

共 59 条

[1] Genetic effects on gene expression across human tissues [J].

Aguet, Francois ;

Brown, Andrew A. ;

Castel, Stephane E. ;

Davis, Joe R. ;

He, Yuan ;

Jo, Brian ;

Mohammadi, Pejman ;

Park, Yoson ;

Parsana, Princy ;

Segre, Ayellet V. ;

Strober, Benjamin J. ;

Zappala, Zachary ;

Cummings, Beryl B. ;

Gelfand, Ellen T. ;

Hadley, Kane ;

Huang, Katherine H. ;

Lek, Monkol ;

Li, Xiao ;

Nedzel, Jared L. ;

Nguyen, Duyen Y. ;

Noble, Michael S. ;

Sullivan, Timothy J. ;

Tukiainen, Taru ;

MacArthur, Daniel G. ;

Getz, Gad ;

Management, Nih Program ;

Addington, Anjene ;

Guan, Ping ;

Koester, Susan ;

Little, A. Roger ;

Lockhart, Nicole C. ;

Moore, Helen M. ;

Rao, Abhi ;

Struewing, Jeffery P. ;

Volpi, Simona ;

Collection, Biospecimen ;

Brigham, Lori E. ;

Hasz, Richard ;

Hunter, Marcus ;

Johns, Christopher ;

Johnson, Mark ;

Kopen, Gene ;

Leinweber, William F. ;

Lonsdale, John T. ;

McDonald, Alisa ;

Mestichelli, Bernadette ;

Myer, Kevin ;

Roe, Bryan ;

Salvatore, Michael ;

Shad, Saboor .

NATURE, 2017, 550 (7675) :204-+

[2] Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer [J].

Amundadottir, Laufey ;

Kraft, Peter ;

Stolzenberg-Solomon, Rachael Z. ;

Fuchs, Charles S. ;

Petersen, Gloria M. ;

Arslan, Alan A. ;

Bueno-de-Mesquita, H. Bas ;

Gross, Myron ;

Helzlsouer, Kathy ;

Jacobs, Eric J. ;

LaCroix, Andrea ;

Zheng, Wei ;

Albanes, Demetrius ;

Bamlet, William ;

Berg, Christine D. ;

Berrino, Franco ;

Bingham, Sheila ;

Buring, Julie E. ;

Bracci, Paige M. ;

Canzian, Federico ;

Clavel-Chapelon, Francoise ;

Clipp, Sandra ;

Cotterchio, Michelle ;

de Andrade, Mariza ;

Duell, Eric J. ;

Fox, John W., Jr. ;

Gallinger, Steven ;

Gaziano, J. Michael ;

Giovannucci, Edward L. ;

Goggins, Michael ;

Gonzalez, Carlos A. ;

Hallmans, Goran ;

Hankinson, Susan E. ;

Hassan, Manal ;

Holly, Elizabeth A. ;

Hunter, David J. ;

Hutchinson, Amy ;

Jackson, Rebecca ;

Jacobs, Kevin B. ;

Jenab, Mazda ;

Kaaks, Rudolf ;

Klein, Alison P. ;

Kooperberg, Charles ;

Kurtz, Robert C. ;

Li, Donghui ;

Lynch, Shannon M. ;

Mandelson, Margaret ;

McWilliams, Robert R. ;

Mendelsohn, Julie B. ;

Michaud, Dominique S. .

NATURE GENETICS, 2009, 41 (09) :986-U47

[3]

[Anonymous], 2020, BMC MED GENET, DOI DOI 10.1186/S12864-020-6677-Y

[4] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[5] Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics [J].

Barbeira, Alvaro N. ;

Dickinson, Scott P. ;

Bonazzola, Rodrigo ;

Zheng, Jiamao ;

Wheeler, Heather E. ;

Torres, Jason M. ;

Torstenson, Eric S. ;

Shah, Kaanan P. ;

Garcia, Tzintzuni ;

Edwards, Todd L. ;

Stahl, Eli A. ;

Huckins, Laura M. ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Im, Hae Kyung .

NATURE COMMUNICATIONS, 2018, 9

[6] A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse [J].

Nolan, PM ;

Peters, J ;

Strivens, M ;

Rogers, D ;

Hagan, J ;

Spurr, N ;

Gray, IC ;

Vizor, L ;

Brooker, D ;

Whitehill, E ;

Washbourne, R ;

Hough, T ;

Greenaway, S ;

Hewitt, M ;

Liu, XH ;

McCormack, S ;

Pickford, K ;

Selley, R ;

Wells, C ;

Tymowska-Lalanne, Z ;

Roby, P ;

Glenister, P ;

Thornton, C ;

Thaung, C ;

Stevenson, JA ;

Arkell, R ;

Mburu, P ;

Hardisty, R ;

Kiernan, A ;

Erven, H ;

Steel, KP ;

Voegeling, S ;

Guenet, JL ;

Nickols, C ;

Sadri, R ;

Naase, M ;

Isaacs, A ;

Davies, K ;

Browne, M ;

Fisher, EMC ;

Martin, J ;

Rastan, S ;

Brown, SDM ;

Hunter, J .

NATURE GENETICS, 2000, 25 (04) :440-443

[7] Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer [J].

Childs, Erica J. ;

Mocci, Evelina ;

Campa, Daniele ;

Bracci, Paige M. ;

Gallinger, Steven ;

Goggins, Michael ;

Li, Donghui ;

Neale, Rachel E. ;

Olson, Sara H. ;

Scelo, Ghislaine ;

Amundadottir, Laufey T. ;

Bamlet, William R. ;

Bijlsma, Maarten F. ;

Blackford, Amanda ;

Borges, Michael ;

Brennan, Paul ;

Brenner, Hermann ;

Bueno-de-Mesquita, H. Bas ;

Canzian, Federico ;

Capurso, Gabriele ;

Cavestro, Giulia M. ;

Chaffee, Kari G. ;

Chanock, Stephen J. ;

Cleary, Sean P. ;

Cotterchio, Michelle ;

Foretova, Lenka ;

Fuchs, Charles ;

Funel, Niccola ;

Gazouli, Maria ;

Hassan, Manal ;

Herman, Joseph M. ;

Holcatova, Ivana ;

Holly, Elizabeth A. ;

Hoover, Robert N. ;

Hung, Rayjean J. ;

Janout, Vladimir ;

Key, Timothy J. ;

Kupcinskas, Juozas ;

Kurtz, Robert C. ;

Landi, Stefano ;

Lu, Lingeng ;

Malecka-Panas, Ewa ;

Mambrini, Andrea ;

Mohelnikova-Duchonova, Beatrice ;

Neoptolemos, John P. ;

Oberg, Ann L. ;

Orlow, Irene ;

Pasquali, Claudio ;

Pezzilli, Raffaele ;

Rizzato, Cosmeri .

NATURE GENETICS, 2015, 47 (08) :911-+

[8] Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control [J].

Croteau-Chonka, Damien C. ;

Qiu, Weiliang ;

Martinez, Fernando D. ;

Strunk, Robert C. ;

Lemanske, Robert F., Jr. ;

Liu, Andrew H. ;

Gilliland, Frank D. ;

Millstein, Joshua ;

Gauderman, W. James ;

Ober, Carole ;

Krishnan, Jerry A. ;

White, Steven R. ;

Naureckas, Edward T. ;

Nicolae, Dan L. ;

Barnes, Kathleen C. ;

London, Stephanie J. ;

Barraza-Villarreal, Albino ;

Careyl, Vincent J. ;

Weiss, Scott T. ;

Raby, Benjamin A. .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2017, 195 (02) :179-188

[9] Pore-forming activity and structural autoinhibition of the gasdermin family [J].

Ding, Jingjin ;

Wang, Kun ;

Liu, Wang ;

She, Yang ;

Sun, Qi ;

Shi, Jianjin ;

Sun, Hanzi ;

Wang, Da-Cheng ;

Shao, Feng .

NATURE, 2016, 535 (7610) :111-+

[10]

Dressman MA, 2003, CANCER RES, V63, P2194

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