Abstract
The “writers” of four types of adenosine (A)-related RNA modifications (N6-methyladenosine, N1-methyladenosine, alternative polyadenylation, as well as A-to-inosine RNA editing) are closely related to the tumorigenesis and progression of many cancer types, including skin cutaneous melanoma (SKCM). However, the potential roles of the crosstalk between these RNA modification “writers” in the tumor microenvironment (TME) remain unclear. The RNA modification patterns were identified using an unsupervised clustering method. Subsequently, based on differentially expressed genes responsible for the aforementioned RNA modification patterns, an RNA modification “writer” scoring model (W_Score) was constructed to quantify the RNA modification-associated subtypes in individual patients. Moreover, a correlation analysis for W_Score and the TME characteristics, clinical features, molecular subtypes, drug sensitivities, immune responses, and prognosis was performed. We identified three RNA modification patterns, corresponding to distinct tumor immune microenvironment characteristics and survival outcomes. Based on the W_Score score, which was extracted from the RNA modification-related signature genes, patients with SKCM were divided into high- and low-W_Score groups. The low-W_Score group was characterized by better survival outcomes and strengthened immunocyte infiltration. Further analysis showed that the low-W_Score group was positively associated with higher tumor mutation burden and PD-L1 expression. Of note, two immunotherapy cohorts demonstrated that patients with low W_Score exhibited long-term clinical benefits and an enhanced immune response. This study is the first to systematically analyze four types of A-related RNA modifications in SKCM, revealing that these “writers” essentially contribute to TME complexity and diversity. We quantitatively evaluated the RNA modification patterns in individual tumors, which could aid in developing personalized immunotherapy strategies for patients.
Highlights
Worldwide, there were 324,635 and 57,043 estimated new skin cutaneous melanoma (SKCM) cases and deaths, respectively, in 2020 (Sung et al, 2021)
The patients were divided into two groups, and enrichment analysis via Gene Set Variation Analysis (GSVA) revealed that tumor hallmarks associated gene sets, including the KRAS signaling pathway, DNA repair pathway, and the PI3K/AKT/MTOR signaling pathway, were mainly enriched in “writers” mutation group (Supplementary Figure S2C)
The results showed that in the The Cancer Genome Atlas (TCGA) cohort (Supplementary Table S4), the writer cluster B exhibited increased fractions of tumor-infiltrating immune cells (Figure 3A), as well as a higher enrichment score for immunerelated pathways (Figure 3B), which was similar to the findings obtained for the Gene Expression Omnibus (GEO) cohort (GSE65904; Supplementary Figure S4)
Summary
There were 324,635 and 57,043 estimated new skin cutaneous melanoma (SKCM) cases and deaths, respectively, in 2020 (Sung et al, 2021). SKCM accounts for approximately 4% of all cases of skin cancer and is the most fatal subtype of skin cancer (Lin et al, 2021). Previous studies have demonstrated that the occurrence and development of SKCM are related to the accumulation of mutations in gene-modulating signaling pathways, including the Rb, p53, PI3K/AKT, and RAS/MAPK pathways (Dietrich et al, 2018; Chamcheu et al, 2019). The onset of SKCM may be partially attributed to somatic mutations, epigenetic changes in cancer-related genes are associated with its etiology (de Unamuno Bustos et al, 2018). Increasing evidence has revealed that RNA modification is mechanism that is indispensable for epigenetic regulation, which is involved in tumorigenesis and development of multiple cancers, including SKCM (Gu et al, 2015; Shen et al, 2019)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
