Characterization of m6A RNA Methylation Regulators Predicts Survival and Immunotherapy in Lung Adenocarcinoma

Abstract

N6-methyladenosine (m6A) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between m6A modification and tumorigenesis and response to immunotherapy. However, the overall influence of m6A regulators on the tumor microenvironment and their effect on the response to immunotherapy in lung adenocarcinoma remains to be explored. Here, we comprehensively analyzed the m6A modification patterns of 936 lung adenocarcinoma samples based on 24 m6A regulators. First, we described the features of genetic variation in these m6A regulators. Many m6A regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three m6A modification patterns using a consensus clustering method. m6A cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, m6A cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. m6A cluster C was characterized by activation of the immune system and a higher stromal cell score. Surprisingly, patients who received radiotherapy had a better prognosis than patients without radiotherapy only in the m6A cluster C group. Subsequently, we constructed an m6A score model that qualified the m6A modification level of individual samples by using principal component analysis algorithms. Patients with high m6A score were characterized by enhanced immune cell infiltration and prolonged survival time and were associated with lower tumor mutation burden and PD-1/CTLA4 expression. The combination of the m6A score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high m6A score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that m6A modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of m6A modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our m6A score model demonstrated that the level of immune cell infiltration plays a significant role in cancer immunotherapy and provides a basis to increase the efficiency of current immune therapies and promote the clinical success of immunotherapy.

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.…”

“…Recent studies have also implicated m 7 G in tumor progression and development in lung cancer, intrahepatic cholangiocarcinoma (ICC), hepatocellular carcinoma (HCC), bladder cancer, and colon cancer ( 16 – 21 ). Using bioinformatic analyses, accumulating studies have determined that the RNA modification-related gene signatures, such as m 6 A, m 1 A, and m 5 C, can predict the prognosis and guide therapeutic decisions in most cancers, including LUAD ( 22 – 27 ). However, to the best of our knowledge, there are no studies reporting the predictive role of m 7 G-related regulatory genes in any malignancies.…”

Roles and therapeutic implications of m6A modification in cancer immunotherapy

“…In addition to the aforementioned regulatory pathways validated experimentally, researchers have analyzed the relationship between m6A methylation modification and the expression of immunotherapeutic targets, such as PD-1, PD-L1, CTLA4, TIGIT, and LAG3 by bioinformatics, revealing the important roles of m6A modification patterns in the anti-tumor immunotherapy strategy for various cancers. For instance, the m6A score or m6A-related high/low-risk subgroup, based on the expression of m6A methylation-related genes, was characterized by differential expression of several immune checkpoints, including PD-1, PD-L1, and CTLA-4 in head and neck squamous cell carcinoma ( 141 ), bladder cancer ( 142 – 144 ), lung adenocarcinoma ( 145 ), clear cell renal cell carcinoma ( 146 , 147 ), glioblastoma multiforme ( 148 ), HCC ( 149 ), gastric cancer ( 150 ), and small cell lung cancer ( 151 ). The aberrant expression of these immune checkpoints plays an important role in the efficacy of anti-PD-L1 immune checkpoint therapy, considered a predictor for the prognosis in patients treated with ICIs.…”

Development and Validation of Prognostic Model for Lung Adenocarcinoma Patients Based on m6A Methylation Related Transcriptomics

“…Lung cancer ranks as the major cause of cancer death, accounting for almost a quarter of cancer deaths ( 1 ). Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, accounting for more than 40% of lung cancer incidence ( 2 ).N 6 -methyladenosine (m 6 A), the most abundant form of posttranscriptional RNA modification in eukaryotes, plays an important role in a variety of biological processes by regulating the translation, processing, splicing, stabilization, and degradation of target RNA ( 3 ). The abundance and effects of m 6 A methylation modification on RNA are maintained by its methyltransferases (‘writers’), binding proteins (‘readers’), and demethylases (‘erasers’) ( 4 ).…”