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<p>Gliomas are the most common primary brain tumours with considerable heterogeneity and aggressive clinical behaviour. The recent WHO 2021 classification emphasises molecular markers, such as IDH1/2 mutations and 1p/19q codeletion, for refined diagnosis and prognosis. Among emerging regulatory mechanisms, RNA N6-methyladenosine (m6A) modifications and their interplay with SETD2 have attracted attention for their roles in tumour progression. A comprehensive analysis of SETD2 and seven m6A regulators (writers: METTL3, METTL14, WTAP; erasers: ALKBH5, FTO; readers: YTHDF1, YTHDF2) was conducted using quantitative real-time PCR (qRT-PCR) on glioma tissue samples. Global m6A levels were assessed using dot blot assays, and data from public databases (GlioVis, GENT2, TCGA) were employed to assess diagnostic, prognostic, and functional relevance. SETD2 and m6A regulators (METTL3, WTAP, ALKBH5, YTHDF1, and YTHDF2) displayed subtype-specific expression, with increased expression of in Astrocytoma IDH mutant grade 3 and 4. Dot blot assays revealed that IDH-mutant astrocytomas exhibit increased m6A levels as tumour grade increases. A strong correlation was observed between SETD2 and core m6A components (Pearson r: METTL3 = 0.75, WTAP = 0.98, ALKBH5 = 0.91, YTHDF1 = 0.63, and YTHDF2 = 0.9645, p &lt; 0.05), suggesting co-transcriptional m6A deposition. GO analysis highlighted enrichment in RNA stability, methylation, and degradation pathways. This study provides preliminary evidence for a possible coordinated epigenetic–epitranscriptomic axis involving SETD2 and the m6A RNA methylation machinery in driving IDH-mutant glioma progression, highlighting SETD2 as both a key regulator of m6A dynamics and a diagnostic biomarker.</p>

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Molecular signature of SETD2 and m6A modifiers in the pathogenesis of different grades of adult-type diffuse gliomas

  • 期刊论文

  • 发表日期：

    2026年4月16日

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  • Subhadra Kumari,
  • Kirthik Roshan M,
  • Rituparna Pal,
  • Sushila Jaiswal,
  • Awadhesh Jaiswal,
  • Santosh Kumar,
  • Srinivasan Muthuswamy

摘要

Gliomas are the most common primary brain tumours with considerable heterogeneity and aggressive clinical behaviour. The recent WHO 2021 classification emphasises molecular markers, such as IDH1/2 mutations and 1p/19q codeletion, for refined diagnosis and prognosis. Among emerging regulatory mechanisms, RNA N6-methyladenosine (m6A) modifications and their interplay with SETD2 have attracted attention for their roles in tumour progression. A comprehensive analysis of SETD2 and seven m6A regulators (writers: METTL3, METTL14, WTAP; erasers: ALKBH5, FTO; readers: YTHDF1, YTHDF2) was conducted using quantitative real-time PCR (qRT-PCR) on glioma tissue samples. Global m6A levels were assessed using dot blot assays, and data from public databases (GlioVis, GENT2, TCGA) were employed to assess diagnostic, prognostic, and functional relevance. SETD2 and m6A regulators (METTL3, WTAP, ALKBH5, YTHDF1, and YTHDF2) displayed subtype-specific expression, with increased expression of in Astrocytoma IDH mutant grade 3 and 4. Dot blot assays revealed that IDH-mutant astrocytomas exhibit increased m6A levels as tumour grade increases. A strong correlation was observed between SETD2 and core m6A components (Pearson r: METTL3 = 0.75, WTAP = 0.98, ALKBH5 = 0.91, YTHDF1 = 0.63, and YTHDF2 = 0.9645, p < 0.05), suggesting co-transcriptional m6A deposition. GO analysis highlighted enrichment in RNA stability, methylation, and degradation pathways. This study provides preliminary evidence for a possible coordinated epigenetic–epitranscriptomic axis involving SETD2 and the m6A RNA methylation machinery in driving IDH-mutant glioma progression, highlighting SETD2 as both a key regulator of m6A dynamics and a diagnostic biomarker.