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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.
Abstract:
N6-Methyladenosine (m6A) is the most abundant internal modification in mRNAs. Despite accumulating evidence for the profound impact of m6A on cancer biology, there are conflicting reports that alterations in genes encoding the m6A machinery proteins can either promote or suppress cancer, even in the same tumor type. Using data from The Cancer Genome Atlas, we performed a pan-cancer investigation of 15 m6A core factors in nearly 10000 samples from 31 tumor types to reveal underlying cross-tumor patterns. Altered expression, largely driven by copy number variations at the chromosome arm level, results in the most common mode of dysregulation of these factors. YTHDF1, YTHDF2, YTHDF3 and VIRMA are the most frequently altered factors and the only ones to be uniquely altered when tumors are grouped according to the expression pattern of the m6A factors. These genes are also the only ones with coherent, pan-cancer predictive power for progression-free survival. On the contrary, METTL3, the most intensively studied m6A factor as a cancer target, shows much lower levels of alteration and no predictive power for patient survival. Therefore, we propose the non-enzymatic YTHDF and VIRMA genes as preferred subjects to dissect the role of m6A in cancer and as priority cancer targets.
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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