Methylation in Cancer
Focal hypermethylation silences tumor suppressors. Global hypomethylation unleashes oncogenes and transposons.
“The goal is not to methylate everything. The goal is to regulate the right genes, in the right tissues, at the right time, at the right intensity.”
MLH1
HyperColorectal (Lynch-like)
Promoter hypermethylation silences mismatch repair.
Clinical: Microsatellite instability (MSI-high) → predicts response to immune checkpoint inhibitors.
BRCA1
HyperTriple-negative breast / ovarian
Promoter methylation phenocopies BRCA1 loss-of-function.
Clinical: BRCAness → PARP inhibitor sensitivity.
MGMT
HyperGlioblastoma
Silencing of MGMT removes the alkyl-repair enzyme.
Clinical: Predicts response to temozolomide; standard-of-care biomarker.
CDKN2A (p16)
HyperMany solid tumors
Cell-cycle brake silenced → uncontrolled G1→S transition.
Clinical: Early event in lung, head-and-neck, pancreatic, melanoma.
LINE-1 / SINE
HypoMost carcinomas
Global hypomethylation reactivates transposons → genomic instability.
Clinical: LINE-1 hypomethylation correlates with poor prognosis.
MYC / RAS enhancers
HypoLeukemia, breast, colon
Loss of methylation at oncogene enhancers → overexpression.
Clinical: Drives proliferation and metabolic reprogramming.
In cancer, the cell forgets which genes should stay quiet and which should stay active — an 'epigenetic amnesia'.