DNA Methylation in Cancer: Silencing and Instability

Two Opposite Changes at Once

Normal cells keep most CpG-dense promoter regions (CpG islands) unmethylated and active, while methylating repetitive elements and gene deserts to keep them quiet. Cancer reverses this on both fronts.

Focal hypermethylation of tumour-suppressor promoters, for example CDKN2A, MLH1 or BRCA1, silences those genes as effectively as a deletion. Simultaneously, global hypomethylation reactivates transposable elements, promotes chromosomal instability and can switch on genes that should be off.

How It Arises

Methylation is written by the DNMT enzymes and reversed via the TET enzymes. Altered expression or mutation of these, metabolic changes that affect the cofactors they need, and mutations in chromatin regulators that guide them all contribute.

IDH1 and IDH2 mutations are a clear example: the oncometabolite they produce inhibits TET enzymes and Jumonji demethylases, causing a hypermethylator phenotype.

Diagnostic and Detection Uses

Genome-wide methylation profiling is now a routine classifier for central nervous system tumours and sarcomas, often resolving cases that histology cannot. Single-gene methylation tests such as MGMT promoter status guide treatment in glioblastoma.

Methylation patterns in circulating DNA are the basis of several multi-cancer early-detection tests, because they can indicate both the presence and the tissue of origin of a tumour.

From Methylation to Therapy

DNA methylation is druggable in a limited way. The hypomethylating agents azacitidine and decitabine deplete DNMT1 and are standard in higher-risk myelodysplastic syndromes and, with venetoclax, in acute myeloid leukaemia; their effect in solid tumours has been weak. IDH inhibitors indirectly reduce the hypermethylation caused by mutant IDH.

A promoter-hypermethylation finding on a report is occasionally directly useful — MGMT status in glioblastoma is the clearest case — but more often it explains why a tumour suppressor is silent despite an intact sequence, or supports a methylation-based tumour classification. The drug side is covered in the hypomethylating-agents guide.

Key Takeaways

• ·Cancers combine focal promoter hypermethylation with genome-wide hypomethylation.
• ·Promoter hypermethylation can silence tumour suppressors as completely as a mutation or deletion.
• ·Methylation profiling is used for tumour classification and for circulating-DNA cancer detection.