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Published on: February 1, 2020
Tumor-type specific methylation patterns of MTAP in human samples and cell lines
Luis Álvarez-Carrión1, Dalma Müller2, Manuel Pedregal3
1CANMET Research Group, Cátedra INTHEOS-START-CEU de Oncología de Precision, Departamento de Ciencias Médicas Básicas, Facultad de Medicina, Instituto de Medicina Molecular Aplicada (IMMA), Universidad San Pablo-CEU, CEU Universities ES, Urbanización Montepríncipe, 28660, Boadilla del Monte, Spain.
Methylthioadenosine phosphorylase (MTAP) loss creates a dependency on PRMT5. This study reveals promoter hypermethylation as a key MTAP inactivation mechanism, suggesting epigenetic profiling for MTAP-based precision oncology.
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- Loss of methylthioadenosine phosphorylase (MTAP) creates a therapeutic dependency on PRMT5.
- Current patient selection for MTAP-targeted therapies relies solely on MTAP genomic deletion.
- Alternative mechanisms of MTAP inactivation remain underexplored.
Purpose of the Study:
- To identify alternative, copy-number-independent mechanisms of MTAP inactivation.
- To investigate the role of DNA methylation in MTAP silencing.
- To support the integration of epigenetic profiling into MTAP-based precision oncology.
Main Methods:
- Integrated analysis of DNA methylation and gene expression data.
- Utilized datasets from TCGA, TARGET, and ENCODE.
- Focused on promoter-proximal CpG site (cg25162921) methylation and MTAP mRNA expression correlation.
Main Results:
- Identified frequent hypermethylation at promoter-proximal CpG site cg25162921.
- Demonstrated a strong inverse correlation between cg25162921 hypermethylation and MTAP mRNA expression.
- Observed this epigenetic silencing mechanism across multiple tumor types and cell lines, including lung squamous cell carcinoma and glioblastoma.
Conclusions:
- Promoter hypermethylation is a significant copy-number-independent mechanism for MTAP inactivation.
- Epigenetic profiling of tumor samples can identify alternative MTAP silencing pathways.
- Findings support the evaluation of epigenetic markers for patient stratification in MTAP-targeted therapies.
