INTRODUCTION

Promoter methylation is a key mechanism regulating gene expression. In cancer, hypermethylation silences tumor suppressors, while global hypomethylation induces genomic instability. It is known that HPV+ and - cancers exhibit distinct methylation patterns. This study characterizes the methylation of DNA repair genes in HPV+ and - HNSCC and evaluates potential therapeutic implications.

MATERIAL & METHODS

DNA methylation and mRNA expression data from the TCGA Firehose Legacy dataset were analyzed to identify differentially methylated genes in HPV+ and HPV- HNSCC. Gene Ontology and pathway enrichment analyses were performed using the DAVID web platform. Negative correlation between methylation and mRNA expression was used to determine transcriptional repression. Hypermethylated, transcriptionally repressed genes were analyzed for drug sensitivity associations.

RESULTS

Functional annotation of hypermethylated genes in HPV- HNSCC showed significant enrichment for DNA repair (q-value=8,5e-3; enrichment score=3,41) as well as replication, transcriptional regulation and apoptosis. Several branches of the DNA repair system are transcriptionally repressed; most affected are the double-strand repair, Fanconi anemia (FA) pathway, nucleotide-excision repair and translesion synthesis. Further, methylation of key pathway members is associated with drug sensitivity. In contrast, HPV+ cancers exhibit enriched expression of genes related to DNA repair, chromosome maintenance and stability. Hypermethylation is observed in genes involved in cell adhesion and extracellular matrix.

DISCUSSION

HPV+ and - HNSCC exhibit distinct methylation patterns. DNA repair gene repression in HPV- cancers is linked to drug sensitivity and presents a potential therapeutic opportunity.

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