Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer Journal Article
| Authors: | Li, D.; Duell, E. J.; Yu, K.; Risch, H. A.; Olson, S. H.; Kooperberg, C.; Wolpin, B. M.; Jiao, L.; Dong, X.; Wheeler, B.; Arslan, A. A.; Bueno-de-Mesquita, H. B.; Fuchs, C. S.; Gallinger, S.; Gross, M.; Hartge, P.; Hoover, R. N.; Holly, E. A.; Jacobs, E. J.; Klein, A. P.; LaCroix, A.; Mandelson, M. T.; Petersen, G.; Zheng, W.; Agalliu, I.; Albanes, D.; Boutron-Ruault, M. C.; Bracci, P. M.; Buring, J. E.; Canzian, F.; Chang, K.; Chanock, S. J.; Cotterchio, M.; Gaziano, J. M.; Giovannucci, E. L.; Goggins, M.; Hallmans, G.; Hankinson, S. E.; Hoffman Bolton, J. A.; Hunter, D. J.; Hutchinson, A.; Jacobs, K. B.; Jenab, M.; Khaw, K. T.; Kraft, P.; Krogh, V.; Kurtz, R. C.; Robert, R. McWilliams; Mendelsohn, J. B.; Patel, A. V.; Rabe, K. G.; Riboli, E.; Shu, X. O.; Tjønneland, A.; Tobias, G. S.; Trichopoulos, D.; Virtamo, J.; Visvanathan, K.; Watters, J.; Yu, H.; Zeleniuch-Jacquotte, A.; Amundadottir, L.; Stolzenberg-Solomon, R. Z. |
| Article Title: | Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer |
| Abstract: | 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. © 2012. |
| Keywords: | signal transduction; controlled study; unclassified drug; major clinical study; single nucleotide polymorphism; pancreas cancer; cell cycle; dna repair; apoptosis; transforming growth factor beta; sonic hedgehog protein; genetic association; genetic variability; notch receptor; phosphatidylinositol 3 kinase; carcinogenesis; th2 cell; genetic susceptibility; th1 cell; genetic risk; transcription factor pdx 1; wnt protein; mitogen activated protein kinase kinase; helicobacter pylori; liver receptor homolog 1; mitogen activated protein kinase kinase 8 |
| Journal Title: | Carcinogenesis |
| Volume: | 33 |
| Issue: | 7 |
| ISSN: | 0143-3334 |
| Publisher: | Oxford University Press |
| Date Published: | 2012-07-01 |
| Start Page: | 1384 |
| End Page: | 1390 |
| Language: | English |
| DOI: | 10.1093/carcin/bgs151 |
| PROVIDER: | scopus |
| PMCID: | PMC3405651 |
| PUBMED: | 22523087 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 October 2012" - "CODEN: CRNGD" - "Source: Scopus" |
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