title: Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: a gene- and pathway-based interaction analysis of GWAS data.
abstract: Cigarette smoking is the best established modifiable risk factor for pancreatic cancer. Genetic factors that underlie smoking-related pancreatic cancer have previously not been examined at the genome-wide level. Taking advantage of the existing Genome-wide 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 P interaction < 0.0005. Five intergenic region SNPs and two SNPs of the EVC and KCNIP4 genes had P interaction < 0.00003. In IPA analysis of genes with nominal interactions with smoking, axonal guidance signaling $$\left(P=2.12\times 1{0}^{-7}\right)$$ and α-adrenergic signaling $$\left(P=2.52\times 1{0}^{-5}\right)$$ 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.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Tang
authors.forename: Peng
authors.initials: P
authors.lastname: Wei
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Duell
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.forename: Sara H
authors.initials: SH
authors.lastname: Olson
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holly
authors.forename: Gloria
authors.initials: G
authors.lastname: Petersen
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.forename: Mazda
authors.initials: M
authors.lastname: Jenab
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Boutron-Ruault
authors.forename: Rudolph
authors.initials: R
authors.lastname: Kaaks
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.forename: Malin
authors.initials: M
authors.lastname: Sund
authors.forename: Petra H M
authors.initials: PH
authors.lastname: Peeters
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Donghui
authors.initials: D
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D015398:Signal Transduction; D012907:Smoking