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

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.

Fas-associated factor 1 inhibits tumor growth by suppressing Helicobacter pylori-induced activation of NF-κB signaling in human gastric carcinoma

“…Our results suggest that loss of FAF1 expression is related to greater NF-κB activation during gastric carcinogenesis, which is consistent with previous work [20]. Our finding that FAF1 is suppressed by H. pylori -activated NF-κB signaling in gastric carcinogenesis, coupled with previous reports that FAF1 inhibits NF-κB activity by interfering with nuclear translocation of p65 [21] and IKKβ [22], suggests a new set of interactions that can be analyzed more deeply to gain more insights into how gastric cancer progresses.…”

The Clinical Utilization of Circulating Cell Free DNA (CCFDNA) in Blood of Cancer Patients

“…Even in triple negative breast cancer there are novel variants as a result of splicing [85–89]. In gastric tumors, SNP variations in the Fas signaling pathway are consistent with associations of altered Fas signaling and/or apoptosis with risk of gastric carcinoma [90]. In hepatocellular carcinoma, the presence of A1762T/G1764A alteration was independently associated with the risk of HCC [91].…”

Associations between interleukin gene polymorphisms and the risk of gastric cancer: A meta‐analysis

“…Nevertheless, there is accumulating evidence to support that genetic factors play an important role in its pathogenesis. Firstly, numerous genetic loci have been found to be associated with an increased risk of GC. Secondly, family clustering of GC is not uncommon, and positive family history in first‐degree relatives has also been proved to be a strong independent risk factor of GC . Overall, these findings jointly indicate that genetic predisposition to GC is crucial for its occurrence and development.…”