Analysis of m6A modulator-mediated methylation modification patterns and the tumor microenvironment in lung adenocarcinoma.

ABSTRACT

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. In the development and progression of LUAD, epigenetic aberration plays a crucial role. However, the function of RNA N6-methyladenosine (m6A) modifications in the LUAD progression is unknown. The m6A regulator modification patterns in 955 LUAD samples were analyzed comprehensively. Patterns were systematically correlated with the tumor microenvironment (TME) cell-infiltration characteristics. Using principal component analysis algorithms, the m6Ascore was generated to quantify m6A modification patterns in individual tumors. Then, their values for predicting prognoses and therapeutic response in LUAD patients were assessed. Three distinct m6A modification patterns in LUAD were identified. Among them, the prognosis of m6Acluster C was the best, while the prognosis of m6Acluster A was the worst. Interestingly, the characterization of TME cell infiltration and biological behavior differed among the three patterns. To evaluate m6A modification patterns within individual tumors, an m6Ascore signature was constructed. The results showed that the high m6Ascore group was associated with a better prognosis; tumor somatic mutations and tumor microenvironment differed significantly between the high- and low- m6Ascore groups. Furthermore, in the cohort with anti-CTLA-4 treatment alone, patients with a high m6Ascore had higher ICI scores, which indicated significant therapeutic advantage and clinical benefits.