Genetic variants in fas signaling pathway genes and risk of gastric cancer

Paula L. Hyland, Shih Wen Lin, Nan Hu, Han Zhang, Lemin Wang, Hua Su, Chaoyu Wang, Ti Ding, Ze Zhong Tang, Jin Hu Fan, You Lin Qiao, Xiaoqin Xiong, William Wheeler, Carol Giffen, Kai Yu, Jeff Yuenger, Laurie Burdett, Zhaoming Wang, Stephen J. Chanock, Margaret A. TuckerSanford M. Dawsey, Neal D. Freedman, Alisa M. Goldstein, Christian C. Abnet, Philip R. Taylor

Research output: Contribution to journalArticlepeer-review

Abstract

Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (p = 5.5E-04) and GCA (p = 6.3E-03), but not GNCA (p= 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal p < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal p< 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations. What's new? The bacteria H. pylori is known to cause gastric cancer, but genetic changes can also contribute, particularly in high-risk populations. Identifying these genetic changes in patients could help clinicians make more accurate prognosis of gastric cancer. These authors looked at variation in genes of the Fas signaling pathway, searching for a connection with GC in a high-risk Chinese population. They found that changes in ten specific genes contributed to GC risk in the population, suggesting further work to investigate the functions of those genes.

Original languageEnglish (US)
Pages (from-to)822-831
Number of pages10
JournalInternational Journal of Cancer
Volume134
Issue number4
DOIs
StatePublished - Feb 15 2014

Keywords

  • Fas signaling
  • GWAS
  • gastric cancer
  • gastric cardia
  • gastric noncardia
  • genetic variants
  • pathway genes
  • single nucleotide polymorphisms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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