The aim of this article was to evaluate whether genetic variants in autophagy‐related genes affect the overall survival (OS) of non‐small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy‐related genes for OS in 1,001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype‐Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. We observed that the variants of rs10514231, rs1864182 and rs1864183 were associated with poor lung cancer survival (HR = 1.33, 95% CI = 1.07–1.65; HR = 1.43, 95% CI = 1.13–1.81; HR = 1.38, 95% CI = 1.14–1.68, respectively) and positively correlated with ATG10 expression (all p < 0.05) from GTEx and TCGA datasets. The elevated expression of ATG10 may predict shorter survival time in lung cancer patients in TCGA dataset (HR = 2.10, 95% CI = 1.33–3.29). Moreover, the variants of rs10514231 and rs1864182 were associated with the increased methylation levels of cg17942617 (meQTL), which in turn contributed to the elevated ATG10 expression and decreased survival time. Further functional assays revealed that ATG10 facilitated lung cancer cell proliferation and migration. Our findings suggest that eQTL/meQTL variations of ATG10 could influence lung cancer survival through regulating ATG10 expression.

Most expression quantitative trait locus (eQTL) analyses have been conducted in heterogeneous gastric tissues, limiting understanding of cell-type-specific regulatory mechanisms. Here, we employed a pooled multiplexing strategy to profile 399,683 gastric cells from 203 Chinese individuals using single-cell RNA sequencing (scRNA-seq). We identified 19 distinct gastric cell types and performed eQTL analyses, uncovering 8,498 independent eQTLs, with a considerable fraction (81%, 6,909/8,498) exhibiting cell-type-specific effects. Integration of these eQTLs with genome-wide association studies for gastric cancer (GC) revealed four co-localization signals in specific cell types. Genetically predicted cell-type-specific gene expression identified 15 genes associated with GC risk, including the upregulation of MUC1 exclusively in parietal cells, linked to decreased GC risk. Our findings highlight substantial heterogeneity in the genetic regulation of gene expression across gastric cell types and provide critical cell-type-specific annotations of genetic variants associated with GC risk, offering new molecular insights underlying GC.

Intestinal metaplasia (IM) represents a precancerous condition associated with an increased risk of gastric cancer. A better understanding of whether and how precancerous lesions progress to gastric cancer is crucial for patient stratification and personalized prevention. In this study, we reconstruct evolutionary trajectories of genomic alterations in 330 multiregion matched samples of IM and tumors from 93 patients with gastric cancer. Intestinal-type gastric cancer (IGC) exhibited a higher mutation burden than diffuse-type gastric cancer (DGC), notably in genomically stable patients. IM from genomically stable patients carried more mutations associated with alcohol consumption. The 20 significantly mutated genes identified were classified into three evolutionary patterns. “Maintained” genes (TP53, APC, and PIK3CA) were commonly altered in IM and matched gastric cancer samples in both IGC and DGC, whereas CDH1 mutations were specific to DGC. “Maintained” mutations in IM accelerated gastric cancer progression. Alterations in “IM-favored” genes (MUC6, CFTR, BMP6, and MTRR) were associated with IM development but were negatively selected in gastric cancer. Interestingly, MUC6 mutations were enriched in specific pit cells with upregulation of GKN1 and GKN2. The remaining genes were “gastric cancer–favored” and showed high heterogeneity in gastric cancer. These findings illuminate the genomic evolution from IM to IGC or DGC, providing insights that could guide precancerous lesion surveillance and early prevention strategies. Significance: Comprehensive genomic characterization uncovers maintained and gained alterations during evolution from intestinal metaplasia to gastric cancer, which could serve as predictive biomarkers to identify individuals at high risk of developing cancer.

Long non-coding RNAs (lncRNAs) serve as vital candidates to mediate cancer risk. Here, we aimed to identify the risk single-nucleotide polymorphisms (SNPs)-induced lncRNAs and to investigate their roles in gastric cancer (GC) development. Through integrating the differential expression analysis of lncRNAs in GC tissues and expression quantitative trait loci analysis in normal stomach tissues and GC tissues, as well as genetic association analysis based on GC genome-wide association studies and an independent validation study, we identified four lncRNA-related SNPs consistently associated with GC risk, including SNHG7 [odds ratio (OR) = 1.16, 95% confidence interval (CI): 1.09–1.23], NRAV (OR = 1.11, 95% CI: 1.05–1.17), LINC01082 (OR = 1.16, 95% CI: 1.08–1.22) and FENDRR (OR = 1.16, 95% CI: 1.07–1.25). We further found that a functional SNP rs6489786 at 12q24.31 increases binding of MEOX1 or MEOX2 at a distal enhancer and results in up-regulation of NRAV. The functional assays revealed that NRAV accelerates GC cell proliferation while inhibits GC cell apoptosis. Mechanistically, NRAV decreases the expression of key subunit genes through the electron transport chain, thereby driving the glucose metabolism reprogramming from aerobic respiration to glycolysis. These findings suggest that regulating lncRNA expression is a crucial mechanism for risk-associated variants in promoting GC development.