Remote modulation of lncRNA <i>GCLET</i> by risk variant at 16p13 underlying genetic susceptibility to gastric cancer.

Abstract

The biological effects of susceptibility loci are rarely reported in gastric tumorigenesis. We conducted a large-scale cross-ancestry genetic study in 18,852 individuals and identified the potential causal variant rs3850997 T>G at 16p13 significantly associated with a decreased risk of gastric cancer [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.83 to 0.91, <i>P</i> = 2.13 × 10^-9]. This risk effect was mediated through the mapped long noncoding RNA <i>GCLET</i> (<i>Gastric Cancer Low-Expressed Transcript</i>; OR_indirect = 0.987, 95% CI = 0.975 to 0.999, <i>P</i> = 0.018). Mechanistically, rs3850997 exerted an allele-specific long-range regulatory effect on <i>GCLET</i> by affecting the binding affinity of CTCF. Furthermore, <i>GCLET</i> increased <i>FOXP2</i> expression by competing with miR-27a-3p, and this regulation remarkably affected in vitro, in vivo, and clinical gastric cancer phenotypes. The findings highlight the genetic functions and implications for the etiology and pathology of cancers.