Characteristic of molecular subtypes in lung adenocarcinoma based on m6A RNA methylation modification and immune microenvironment

Abstract

Background Lung adenocarcinoma (LUAD) is a major subtype of lung cancer and closely associated with poor prognosis. N6-methyladenosine (m6A), one of the most predominant modifications in mRNAs, is found to participate in tumorigenesis. However, the potential function of m6A RNA methylation in the tumor immune microenvironment is still murky. Methods The gene expression profile cohort and its corresponding clinical data of LUAD patients were downloaded from TCGA database and GEO database. Based on the expression of 21 m6A regulators, we identified two distinct subgroups by consensus clustering. The single-sample gene-set enrichment analysis (ssGSEA) algorithm was conducted to quantify the relative abundance of the fraction of 28 immune cell types. The prognostic model was constructed by Lasso Cox regression. Survival analysis and receiver operating characteristic (ROC) curves were used to evaluate the prognostic model. Result Consensus classification separated the patients into two clusters (clusters 1 and 2). Those patients in cluster 1 showed a better prognosis and were related to higher immune scores and more immune cell infiltration. Subsequently, 457 differentially expressed genes (DEGs) between the two clusters were identified, and then a seven-gene prognostic model was constricted. The survival analysis showed poor prognosis in patients with high-risk score. The ROC curve confirmed the predictive accuracy of this prognostic risk signature. Besides, further analysis indicated that there were significant differences between the high-risk and low-risk groups in stages, status, clustering subtypes, and immunoscore. Low-risk group was related to higher immune score, more immune cell infiltration, and lower clinical stages. Moreover, multivariate analysis revealed that this prognostic model might be a powerful prognostic predictor for LUAD. Ultimately, the efficacy of this prognostic model was successfully validated in several external cohorts (GSE30219, GSE50081 and GSE72094). Conclusion Our study provides a robust signature for predicting patients’ prognosis, which might be helpful for therapeutic strategies discovery of LUAD.

Construction of a Novel Prognostic Model in Lung Adenocarcinoma Based on 7-Methylguanosine-Related Gene Signatures

“…To compare our prognostic model with other models previously reported in LUAD, we searched four studies primarily focusing on m 6 A-related signatures ( 22 , 31 – 33 ). The number of genes included in these models varied from 3 to 27.…”

“…To compare our prognostic model with other models previously reported in LUAD, four studies primarily focusing on m 6 A-related signatures were selected ( 22 , 31 – 33 ). We extracted the genes included in these prognostic models and used ROC curves and concordance index (C-index) values to compare the predictive accuracy between different models.…”

Characterization of Necroptosis-Related Molecular Subtypes and Therapeutic Response in Lung Adenocarcinoma

“…The classification of LUAD patients based on various biological signatures has been considered a promising method and applied to various studies including immune cell infiltration (ICI) ( Li et al, 2021 ), autophagy ( Zhang M.-Y. et al, 2021 ), pyroptosis ( Dong et al, 2021 ), and m6A RNA methylation ( Zhou et al, 2021 ). Therefore, this study first proposed a necroptosis-related subtype for LUAD based on the clustering expression of NRGs with distinct prognostic and immunological features including TME, ICI, GSVA, and immune checkpoints.…”

“…In addition, multiple biological signatures have also been applied to explore novel molecular subtypes for the prognosis of LUAD, such as immune cell infiltration (ICI) ( Li et al, 2021 ), autophagy ( Zhang M.-Y. et al, 2021 ), pyroptosis ( Dong et al, 2021 ), m6A RNA methylation ( Zhou et al, 2021 ), and so on. However, there is still no study focusing on the role of necroptosis in the subtypes of LUAD patients.…”

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“…In addition, multiple biological signatures have also been applied to explore novel molecular subtypes for the prognosis of LUAD, such as immune cell infiltration (ICI) (Li et al, 2021), autophagy (Zhang M.-Y. et al, 2021), pyroptosis (Dong et al, 2021), m6A RNA methylation (Zhou et al, 2021), and so on. However, there is still no study focusing on the role of necroptosis in the subtypes of LUAD patients.…”