m7G-Associated subtypes, tumor microenvironment, and validation of prognostic signature in lung adenocarcinoma

Abstract

Background: 7-Methylguanosine (m7G) is an important posttranscriptional modification that regulates gene expression and is involved in tumorigenesis and development. Tumor microenvironment has been proven to be highly involved in tumor progression and prognosis. However, how m7G-associated genes affect the tumor microenvironment of patients with lung adenocarcinoma (LUAD) remains to be further clarified.Methods: The genetic alterations of m7G-associated genes and their associations with the prognosis and tumor microenvironment in LUAD patients were systemically analyzed. An m7G-Riskscore was established and analyzed for its performance in disease prognosis and association with patient response to immunotherapy. Expression of the model genes at the protein level was investigated through ex vivo experiments. A nomogram was finally obtained based on the m7G-Riskscore and several significant clinical pathological features.Results: m7G-Associated genes were obtained from five LUAD datasets from The Cancer Genome Atlas and Gene Expression Omnibus databases, and their expression pattern was determined. Based on the m7G-associated genes, three LUAD clusters were defined. The differentially expressed genes from the three clusters were screened and used to further divide the LUAD patients into two gene clusters. It was demonstrated that the alterations of m7G-associated genes were associated with the clinical pathological features, prognosis, and tumor immune infiltration in LUAD patients. An m7G-Riskscore including CAND1, RRM2, and SLC2A1 was obtained with robust and accurate prognostic performance. WB and cell immunofluorescence also showed significant dysregulation of CAND1, RRM2, and SLC2A1 in LUAD. In addition, a nomogram was established to improve the clinical feasibility of the m7G-Riskscore. Correlation analysis revealed that patients with a lower m7G-Riskscore had higher immune and stromal scores, responded well to chemotherapeutics and multiple targeted drugs, and survived longer. Patients with a higher m7G-Riskscore tended to suffer from a higher tumor mutation burden. Furthermore, the m7G-Riskscore exhibited significant associations with immune cell infiltration and cancer stemness.Conclusion: This study systemically analyzed m7G-associated genes and identified their potential role in tumor microenvironment and prognosis in patients with LUAD. The findings of the present study may help better understand LUAD from the m7G perspective and also provide a new thought toward the prognosis and treatment of LUAD.

Three molecular subtypes and a five‐gene signature for hepatocellular carcinoma based on m7G‐related classification

“…In addition, Wang et al analyzed the genetic changes of m7G‐related genes in lung adenocarcinoma patients and their relationship with the TME. Their results demonstrated that m7G‐associated risk scores are significantly related to immune cell infiltration and high‐risk patients tend to show greater tumor mutation burden 56 . These results are similar to ours.…”

“…Their results demonstrated that m7G-associated risk scores are significantly related to immune cell infiltration and highrisk patients tend to show greater tumor mutation burden. 56 These results are similar to ours. In summary, the m7G-related prognostic biomarkers in this study can be used to stratify HCC prognosis and were useful in studying the molecular mechanisms of HCC development.…”

“…55 Despite significant advances in current targeted and immunotherapies, the prognosis for each cancer patient remains unpredictable, which is largely due to differences in the TME. 56 In our study, we found that m7G-associated risk scores were associated with most immune infiltrations. Tang et al showed that m7G regulatory factors are associated with the level of immune infiltration in gliomas, suggesting that m7G regulatory factors are capable of presenting a wide range of immune properties indirectly for the immunomodulation of cancer.…”

“…The TME is composed of immune and stromal cells, and the prognosis of cancer patients is closely associated with immune cell scores and stromal cell scores 55 . Despite significant advances in current targeted and immunotherapies, the prognosis for each cancer patient remains unpredictable, which is largely due to differences in the TME 56 . In our study, we found that m7G‐associated risk scores were associated with most immune infiltrations.…”

Bioinformatics Analysis of the Prognostic Significance of CAND1 in ERα-Positive Breast Cancer

“…The significant negative correlations between CAND1 and several immune cells agree with our previous observation that CAND1 correlates with poor prognosis in ERα-positive breast cancer. Although the correlation between CAND1 and the infiltration of immune cells in breast cancer has not been studied before, a published report showed that the infiltration of CD4 memory T cells and neutrophils correlates positively with CAND1 in lung adenocarcinoma [ 39 ]. This positive correlation might be due to the fact that the authors used a different approach to assess the correlation.…”