Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer.
Carcinogenesis 2012 ; 33: 1384-90.
Li D, Duell EJ, Yu K, Risch HA, Olson SH, Kooperberg C, Wolpin BM, Jiao L, Dong X, Wheeler B, Arslan AA, Bueno-de-Mesquita HB, Fuchs CS, Gallinger S, Gross M, Hartge P, Hoover RN, Holly EA, Jacobs EJ, Klein AP, LaCroix A, Mandelson MT, Petersen G, Zheng W, Agalliu I, Albanes D, Boutron-Ruault MC, Bracci PM, Buring JE, Canzian F, Chang K, Chanock SJ, Cotterchio M, Gaziano JM, Giovannucci EL, Goggins M, Hallmans G, Hankinson SE, Hoffman Bolton JA, Hunter DJ, Hutchinson A, Jacobs KB, Jenab M, Khaw KT, Kraft P, Krogh V, Kurtz RC, McWilliams RR, Mendelsohn JB, Patel AV, Rabe KG, Riboli E, Shu XO, Tjønneland A, Tobias GS, Trichopoulos D, Virtamo J, Visvanathan K, Watters J, Yu H, Zeleniuch-Jacquotte A, Amundadottir L, Stolzenberg-Solomon RZ
DOI : 10.1093/carcin/bgs151
PubMed ID : 22523087
PMCID : PMC3405651
Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10(-6), 1.6 × 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10(-5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.