Copy number variation analysis of m⁶A regulators identified METTL3 as a prognostic and immune‐related biomarker in bladder cancer

Abstract

Growing evidence has demonstrated an indispensable role for N 6methyladenosine (m 6 A) in human diseases, but the copy number variations (CNVs) of m 6 A regulatory genes in bladder cancer (BLCA) remains largely unknown. Methods: We investigated the CNVs on all known m 6 A regulatory genes using the Cancer Genome Atlas (TCGA) database. The association between CNV events and clinicopathological as well as molecular characteristics of BLCA patients were explored. Gene set enrichment analysis (GSEA) was implemented to reveal relative cellular processes. Association between m 6 A regulatory genes and immune infiltrates was analyzed by The Tumor Immune Estimation Resource (TIMER) database. Results: CNV events of m 6 A regulatory genes were frequently observed in BLCA.CNVs of METTL3, METTL14, and METTL16 correlated with molecular characteristics of BLCA patients including TP53 mutation. CNVs of METTL3 associated with the overall survival (OS) of BLCA patients. METTL3 was also associated with several cancer-related cellular processes, including mitotic spindle assembly, G2/M checkpoint, and E2F targets signaling pathway. Besides, the CNVs of m 6 A regulatory genes were correlated with specific kinds of immune infiltrates. Conclusions: There are significant correlations between m 6 A regulatory genes with CNVs and clinicopathological characteristics. METTL3 with CNVs were associated with the immune infiltrates and performed as a prognostic marker in BLCA.

Gene polymorphisms of METTL5 and METTL16 are related to epithelial ovarian cancer risk in South China: A three-center case-control study

“…Bi-allelic variants in METTL5 cause intellectual disability and microcephaly in human [27]. Copy number variation of METTL16 is abundant in bladder cancer patients with mutant TP53 [28]. Inactivating frameshift mutation of METTL16 accelerate the tumorigenesis in colorectal cancer [29].…”

RNA m6Amethylation in cancer

“…The abundance of m 6 A‐related writers, erasers and readers could be candidates for tumor diagnosis. For instance, METTL3 is suggested to be a prognostic and immune‐related biomarker in BCA [ 268 ], while METTL14 is correlated with prognosis in rectal cancer patients and immune infiltration level [ 269 ]. Demethylase ALKBH5 is up‐regulated in several solid tumors and can be a biomarker for some malignant tumor prognosis, such as NSCLC and CRC [ 245 ].…”

The current landscape of m6A modification in urological cancers

“…It was validated that m6A regulators partook in the differentiation and recruitment process of immune cells ( Deng et al, 2022 ). Changes in METTL3 expression were closely associated to the down-regulation of CD4 + T cells, neutrophils, and dendritic cells infiltration level in bladder cancer ( Wang et al, 2021b ), while positively correlated with naive B cells, CD4+ memory resting T cells, and M1 macrophages number and negatively correlated with regulatory T cells and M2 macrophages number in prostate cancer ( Liu et al, 2022c ). The expression of YTHDF2 was positively correlated with B cells, CD8+T cells, CD4+T cells, macrophages, neutrophils, and dendritic cells.…”

“…The prostate cancer patients in the m6A high score group had a worse prognosis than the m6A low score group ( Liu et al, 2022b ). In addition, METTL3’s copy number variations (CNVs) were related to OS ( Wang et al, 2021b ). Various m6A-related LncRNA were also significantly related to RCC patients’ prognostic risk ( Xia et al, 2022 ).…”