m6A Methylation Patterns and Tumor Microenvironment Infiltration Characterization in Clear-Cell Renal Cell Carcinoma

Abstract

Increasing evidence suggests the essential regulation of RNA N6-methyladenosine (m6A) modification in carcinogenesis and immune response. Nevertheless, the potential impacts of these modifications on the tumor microenvironment (TME) immune cell infiltration characteristics in clear-cell renal cell carcinoma (ccRCC) remain unclear. Utilizing a consensus clustering algorithm, we determined three m6A modification patterns and identified three m6A-related gene clusters among 569 ccRCC samples, which were associated with different biological functions and clinical outcomes. Thereafter, the m6A score was constructed using m6A-associated signature genes to accurately exploit the m6A modification patterns within individual tumors. The m6A score was further demonstrated to be noticeably related to ccRCC prognosis. In addition, the m6A score was found to be strongly correlated with tumor mutational burden (TMB), microsatellite instability, immune infiltration, immune checkpoint expression, and immunotherapy response, which was also validated in the pan-cancer analyses. Our findings thoroughly elucidated that m6A modification contributes to tumor microenvironment immune-infiltrating characteristics and prognosis in ccRCC. Assessing the m6A modification patterns of individual patients with ccRCC will offer novel insights into TME infiltration and help develop more effective treatment strategies.

Comprehensive analysis of m6A methylome and transcriptome by Nanopore sequencing in clear cell renal carcinoma

“…43 Furthermore, m 6 A modification has been implicated in tumorigenesis and cancer progression. [44][45][46] While previous studies have investigated the patterns of m 6 A regulatormediated methylation modification in ccRCC, [18][19][20] the comprehensive landscape of genome-wide m 6 A methylome remained elusive.…”

“…Furthermore, m 6 A modification has been implicated in tumorigenesis and cancer progression 44–46 . While previous studies have investigated the patterns of m 6 A regulator‐mediated methylation modification in ccRCC, 18–20 the comprehensive landscape of genome‐wide m 6 A methylome remained elusive. Therefore, in this study, we utilized Nanopore direct RNA‐seq to investigate the transcriptional regulatory mechanism of m 6 A modification in ccRCC.…”

“…16,17 Studies have also demonstrated the correlation between m 6 A modification and the progression of ccRCC. [18][19][20] However, the quantitative analysis of m 6 A modification has been challenging. Previous studies often used methylated RNA immunoprecipitation sequencing (MeRIP-seq) to quantify the modification rate of individual m 6 A sites.…”

“…It plays a crucial role in RNA functions such as RNA maturation, stability, translation, and degradation 16,17 . Studies have also demonstrated the correlation between m 6 A modification and the progression of ccRCC 18–20 . However, the quantitative analysis of m 6 A modification has been challenging.…”

Hypoxia regulates tumour characteristic RNA modifications in ovarian cancers

“…The tumour microenvironment can be stratified by expression patterns of RNA modification-related factors in various cancer types. The expression pattern of RNA modification-related factors correlates not only with immune activity status and tumour mutation burden but also with therapeutic efficacy of immune checkpoint inhibitors and other drugs [14][15][16][17][18].…”