Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

Abstract

We previously reported that some single nucleotide polymorphisms (SNPs) of candidate genes involved in the MTOR complex1 (MTORC1) were associated with risk of gastric cancer (GCa). In the present study, we further evaluated associations of eight potentially functional SNPs of MTOR, MLST8 and RPTOR with survival of 1002 GCa patients and also investigated molecular mechanisms underlying such associations. Specifically, we found that the MTOR rs2536 C allele at the microRNA binding site was independently associated with a 26% reduction of death risk (HR = 0.74, 95% CI = 0.57-0.96, p = 0.022). The results remained noteworthy with a prior false positive probability of 0.1. Genotype-phenotype correlation analysis in 144 patients' adjacent normal gastric tissue samples revealed that the MTOR expression levels were lower in rs2536 TC/CC carriers than that in wild-type TT carriers (p = 0.043). Dual luciferase assays revealed that the rs2536 C allele had a higher binding affinity to microRNA-150, leading to a decreased transcriptional activity of MTOR, compared to the rs2536 T allele. Further functional analysis revealed that MTOR knockdown by small interference RNA impaired proliferation, migration, and invasion ability in GCa cell lines. In conclusion, The MTOR rs2536 T > C change may be a biomarker for survival of Chinese GCa patients, likely by modulating microRNA-induced gene expression silencing. Additional studies are needed to validate our findings.

Remote modulation of WWOX by an intronic variant associated with survival of Chinese gastric cancer patients

“…In particular, WWOX was demonstrated to be closely interacted with mTOR 13 and DNA repair 14 pathways whose genetic variants were our previous focus. Genetic variants in mTOR 9 and DNA repair pathways 6 were found to have significant survival associations with GCa patients in our previous work. However, so far, no study has explored the association between genetic variants in WWOX and the survival of GCa patients.…”

“…Precise prediction of prognosis is extremely necessary in guiding treatment decisions for GCa patients at different death risks 21,22 . We previously found that some SNPs involved in DNA repair 6 and mTOR pathway 9 were survival predictors in GCa patients. Importantly, the present study found genetic variants in WWOX , a gene closely related to DNA repair 14 and mTOR 13 pathway genes, to also be associated with the survival of GCa patients.…”

“…6,7 In addition, genes known to drive the tumorigenesis, proliferation, invasiveness and metastasis ability of cancer cells (eg, nuclear factor-kappa b [NF-κB], Yes-associated protein [YAP], 8 and mammalian target of rapamycin [mTOR]) also harbor genetic variants that influence the death risk of GCa patients, as indicated by our previous work. 9 Because of the limitation of clinical factors as prognostic predictors among GCa patients, it is urgent for us to detect novel genetic variants with utility for survival prediction.…”