Scientific Publications by FDA Staff

J Natl Cancer Inst 2020 Jan 9 [Epub ahead of print]

A transcriptome-wide association study (TWAS) identifies novel candidate susceptibility genes for pancreatic cancer.

Zhong J, Jermusyk A, Wu L, Hoskins JW, Collins I, Mocci E, Zhang M, Song L, Chung CC, Zhang T, Xiao W, Albanes D, Andreotti G, Arslan AA, Babic A, Bamlet WR, Beane-Freeman L, Berndt S, Borgida A, Bracci PM, Brais L, Brennan P, Bueno-de-Mesquita B, Buring J, Canzian F, Childs EJ, Cotterchio M, Du M, Duell EJ, Fuchs C, Gallinger S, Gaziano JM, Giles GG, Giovannucci E, Goggins M, Goodman GE, Goodman PJ, Haiman C, Hartge P, Hasan M, Helzlsouer KJ, Holly EA, Klein EA, Kogevinas M, Kurtz RJ, LeMarchand L, Malats N, Mannisto S, Milne R, Neale RE, et al

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.