The three YTHDF paralogs and VIRMA are strong cross-histotype tumor driver candidates among m6A core genes

Eliana Destefanis1, Denise Sighel1, Davide Dalfovo2

  • 1Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento 38123, Italy.

NAR Cancer
|October 16, 2024
PubMed

Insights

N6-Methyladenosine (m6A) modifications impact cancer, but gene alterations show conflicting roles. Non-enzymatic YTHDF and VIRMA factors, frequently altered, predict patient survival and are priority cancer targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • N6-Methyladenosine (m6A) is the most prevalent internal mRNA modification.
  • m6A's role in cancer is significant but complex, with conflicting reports on m6A machinery proteins.
  • Dysregulation of m6A factors can either promote or suppress tumor development.

Purpose of the Study:

  • To conduct a pan-cancer investigation of 15 m6A core factors across 31 tumor types.
  • To identify cross-tumor patterns in m6A factor alterations and their clinical significance.
  • To determine the most promising m6A-related genes for cancer research and therapeutic targeting.

Main Methods:

  • Utilized The Cancer Genome Atlas (TCGA) data from nearly 10,000 cancer samples.
  • Analyzed copy number variations (CNVs) and gene expression of 15 core m6A machinery proteins.
  • Correlated m6A factor alterations with tumor type and progression-free survival (PFS).

Main Results:

  • Altered gene expression, primarily via chromosome arm-level CNVs, is the most common dysregulation mode for m6A factors.
  • YTHDF1, YTHDF2, YTHDF3, and VIRMA were the most frequently altered factors.
  • YTHDF and VIRMA genes demonstrated coherent, pan-cancer predictive power for PFS, unlike METTL3.

Conclusions:

  • Non-enzymatic m6A factors, specifically YTHDF and VIRMA, are frequently altered in cancer and predict patient survival.
  • These genes offer more consistent insights into m6A's role in cancer compared to enzymatic factors like METTL3.
  • YTHDF and VIRMA represent priority targets for dissecting m6A's function and developing novel cancer therapies.

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