Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients. Issue 2 (30th October 2018) - Cheng, Lei
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. Abstract : What's new? While MTORC1 is known to play an important role in the development of gastric cancer (GCa), its role in GCa progression remains unclear. This study of 1002 Chinese GCa patients demonstrated for the first time that the MTOR rs2536 T > C change predicted better overall survival. Functional studies showed that the 3′UTR of MTOR with rs2536 C had a better binding affinity to miRNA‐150, leading to down‐regulated MTOR expression and a less aggressive phenotype of GCa cells. The MTOR rs2536 T > C change may thus be a biomarker for survival of Chinese GCa patients, likely acting by modulating microRNA‐induced gene expression silencing.