Bioinformatics analyses suggest that mutations in COL12A1 and its miRNAs promote stomach adenocarcinoma via loss of COL12A1 suppression

Objectives: : Stomach adenocarcinoma (STAD) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. It is important to understand its molecular basis better and identify noninvasive biomarkers for targeted therapy. Usually, tumors contain driver genes or passenger genes, which can be regulated by microRNAs (miRNAs). However, the mechanism underlying the interaction between miRNA and their target genes in STAD has not been fully demonstrated. To date, no miRNA-targeted gene mutation sites that promote STAD progression have been reported, and there are no reports of the mutations within the 3 '-UTR of COL12A1 that could contribute to STAD development. Methods: Here, multiple genomic and transcriptomic profiles of STAD patients were downloaded from several reputable online databases and various analyses were conducted, including assessments of mutation rates, copy number variations (CNVs), single-nucleotide polymorphisms (SNPs), RNA secondary structure, protein-protein interaction (PPI), pathway network, differentially expressed genes (DEGs), and patient survival rate. We aimed to evaluate impact of the SNPs on progression of stomach adenocarcinoma. Results: We identified 22 critical DEGs involved in cell-cell and cell-matrix interaction. Seven of these key DEGs, including COL12A1, were associated with poorer overall survival. Interestingly, we found that COL12A1 was targeted by the miRNAs: hsa-miR-130b-5p (which carries the mutations rs1174814901 and rs761813865) and hsa-miR-18a-5p (which carries the mutation rs1198460870). These mutations lead to a change in the secondary structure of the miRNAs. And we also found that the miRNA target sites of COL12A1 were also mutated. These mutations at both miRNAs and COL12A1 likely attenuated their binding capability, leading to compensatory miRNA overexpression in the STAD patients. The miRNA overexpression was further found to be significantly associated with worse survival in STAD patients. Conclusions: Our results suggest that mutations in Col12A1 and its miRNAs promote STAD via loss of COL12A1 suppression, providing new insight into the molecular mechanisms of STAD progression. This finding has significant implications for the development of novel noninvasive diagnostic, prognostic and therapeutic biomarkers.