Abstract
Background: DNA methylation (MET)–mediated transcriptomic disturbance and copy number variations (CNVs) exert a significant influence in stimulating the heterogeneous progression of stomach adenocarcinoma (STAD). Nevertheless, the relation of DNA MET with CNVs, together with its impact on tumor occurrence, is still unclear. Methods: The messenger RNA (mRNA) expression (EXP) profiles, DNA MET, and DNA copy numbers, together with STAD mutation data, were collected from the TCGA official data portal. We employed circular binary segmentation algorithm in “DNAcopy.” library of R package for mapping DNA CNV data at genetic level for all samples based on the segmented CNV data. Stable clusters of samples were recognized using negative matrix factorization cluster analysis based on 50 iterations and the “brunet” method using the MET-correlated (METcor) and CNV-correlated (CNVcor) genes. The R package “iCluster” method was utilized to comprehensively analyze the EXP, MET, and DNA CNV profiles. Results: A total of 313 STAD samples were isolated for checking DNA copy numbers and MET and for measuring EXP. In accordance with our results, we discovered obvious co-regulation of CNVcor genes and METcor counterparts. Apart from that, these genes were subject to multi-omics integration. Meanwhile, three subtypes of STAD were detected and confirmed based on independent data. Among them, the subtype with increased aggressiveness was related to decreased mutation frequencies of ARID1A, PIK3CA, ZFHX3, SPECC1, OBSCN, KMT2D, FSIP2, ZBTB20, TTN, and RANBP2, together with the abnormal levels of JPH3, KCNB1, and PLCXD3. Conclusion: According to the results, these aforementioned genes exerted crucial roles in the development of invasive STAD. Our findings on transcriptomic regulation genomically and epigenetically facilitate the understanding of the STAD pathology from different aspects, which help to develop efficient anti-STAD therapy.
Highlights
DNA methylation (MET)–mediated transcriptomic disturbance and copy number variations (CNVs) exert a significant influence in stimulating the heterogeneous progression of stomach adenocarcinoma (STAD)
The correlation coefficients of DNA MET with related EXP data skewed to the left (Figure 2A), which indicated that DNA CNVs and MET abnormalities positively and negatively modulated transcription, respectively
This study suggested that CNVcor and METcor genes were remarkably effective on transcriptional dysregulation of STAD, which required to be further examined in future studies
Summary
DNA methylation (MET)–mediated transcriptomic disturbance and copy number variations (CNVs) exert a significant influence in stimulating the heterogeneous progression of stomach adenocarcinoma (STAD). The relation of DNA MET with CNVs, together with its impact on tumor occurrence, is still unclear. Gastric cancer (GC), the cancer with high malignancy rate, accounts for about 7.7% of cancer-related deaths in the world in 2020. Related treatments have been developed for GC. It is still the fatal malignant tumor that ranks the fourth place in terms of its mortality globally, which is ascribed to its advanced diagnosis and high morbidity (Sung et al, 2021). Some GC patients present diverse prognostic outcomes and therapeutic responses, even though they are at the same TNM (Tumor Node Metastasis) stage (Shiratsu et al, 2014). The biomarkers for diagnosis and prognosis are in urgent need to improve the STAD diagnosis and to predict the outcomes for patients
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