TY - JOUR
T1 - Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer
T2 - A gene- and pathway-based interaction analysis of GWAS data
AU - Tang, Hongwei
AU - Wei, Peng
AU - Duell, Eric J.
AU - Risch, Harvey A.
AU - Olson, Sara H.
AU - Bueno-de-Mesquita, H. Bas
AU - Gallinger, Steven
AU - Holly, Elizabeth A.
AU - Petersen, Gloria
AU - Bracci, Paige M.
AU - Mcwilliams, Robert R.
AU - Jenab, Mazda
AU - Riboli, Elio
AU - Tjønneland, Anne
AU - Boutron-Ruault, Marie Christine
AU - Kaaks, Rudolph
AU - Trichopoulos, Dimitrios
AU - Panico, Salvatore
AU - Sund, Malin
AU - Peeters, Petra H.M.
AU - Khaw, Kay Tee
AU - Amos, Christopher I.
AU - Li, Donghui
N1 - Funding Information:
National Institutes of Health (RO1 CA98380-05 to D.L.); MD Anderson Cancer Center Support Grant CA016672; R01 grants (CA169122 and HL116720 to P.W.); PO1 grant (5P30CA023108-28) and UO1 grant (7U19CA148127-03 (to C.A.); Sheikh Ahmed Center for Pancreatic Cancer Research at The University of Texas MD Anderson Cancer Center Funds (to D.L.).
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
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U2 - 10.1093/carcin/bgu010
DO - 10.1093/carcin/bgu010
M3 - Article
C2 - 24419231
AN - SCOPUS:84902002285
SN - 0143-3334
VL - 35
SP - 1039
EP - 1045
JO - Carcinogenesis
JF - Carcinogenesis
IS - 5
ER -