Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: A gene- and pathway-based interaction analysis of GWAS data

Hongwei Tang, Peng Wei, Eric J. Duell, Harvey A. Risch, Sara H. Olson, H. Bas Bueno-de-Mesquita, Steven Gallinger, Elizabeth A. Holly, Gloria Petersen, Paige M. Bracci, Robert R. Mcwilliams, Mazda Jenab, Elio Riboli, Anne Tjønneland, Marie Christine Boutron-Ruault, Rudolph Kaaks, Dimitrios Trichopoulos, Salvatore Panico, Malin Sund, Petra H.M. PeetersKay Tee Khaw, Christopher I. Amos, Donghui Li

Research output: Contribution to journalArticle

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Abstract

Cigarette smoking is the best established modifiable risk factor for pancreatic cancer. Genetic factors that underlie smokingrelated pancreatic cancer have previously not been examined at the genome-wide level. Taking advantage of the existing Genomewide association study (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study in 2028 cases and 2109 controls to examine gene-smoking interactions at pathway/gene/single nucleotide polymorphism (SNP) level. Using the likelihood ratio test nested in logistic regression models and ingenuity pathway analysis (IPA), we examined 172 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, 3 manually curated gene sets, 3 nicotine dependency gene ontology pathways, 17 912 genes and 468 114 SNPs. None of the individual pathway/gene/SNP showed significant interaction with smoking after adjusting for multiple comparisons. Six KEGG pathways showed nominal interactions (P < 0.05) with smoking, and the top two are the pancreatic secretion and salivary secretion pathways (major contributing genes: RAB8A, PLCB and CTRB1). Nine genes, i.e. ZBED2, EXO1, PSG2, SLC36A1, CLSTN1, MTHFSD, FAT2, IL10RB and ATXN2 had Pinteraction < 0.0005. Five intergenic region SNPs and two SNPs of the EVC and KCNIP4 genes had Pinteraction < 0.00003. In IPA analysis of genes with nominal interactions actions with smoking, axonal guidance signaling (P=2.12×10-7) and a-adrenergic signaling (P=2.52×10-5) genes were significantly overrepresented canonical pathways. Genes contributing to the axon guidance signaling pathway included the SLIT/ROBO signaling genes that were frequently altered in pancreatic cancer. These observations need to be confirmed in additional data set. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1039-1045
Number of pages7
JournalCarcinogenesis
Volume35
Issue number5
DOIs
StatePublished - Apr 2014

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ASJC Scopus subject areas

  • Cancer Research

Cite this

Tang, H., Wei, P., Duell, E. J., Risch, H. A., Olson, S. H., Bueno-de-Mesquita, H. B., Gallinger, S., Holly, E. A., Petersen, G., Bracci, P. M., Mcwilliams, R. R., Jenab, M., Riboli, E., Tjønneland, A., Boutron-Ruault, M. C., Kaaks, R., Trichopoulos, D., Panico, S., Sund, M., ... Li, D. (2014). Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: A gene- and pathway-based interaction analysis of GWAS data. Carcinogenesis, 35(5), 1039-1045. https://doi.org/10.1093/carcin/bgu010