DNA hypermethylation

Introduction

Hypermethylation of promoter regions with inappropriate transcriptional silencing of genes is seen in many human neoplasms. Nearly 50% of genes with mutations associated with familial forms of cancer show methylation associated silencing in sporadic forms of cancer.

Genes found to be hypermethlated in cancer include:

• VHL (von Hippel Lindau disease tumor suppressor)
• p73
• RASSF1A
• SMARCA3
• APC (adenomatous polyposis coli protein)
• CDKN2A (cyclin dependent kinase inhibitor 2A)
• CDKN2B (cyclin dependent kinase inhibitor 2B)
• GSTP1 (glutathione S-transferase pi)
• RB
• CDH1 (E-cadherin)
• TIMP3 (tissue inhibitor of metalloproteinase 3)
• MLH1 (mutL homologue 1)
• HIC1 (hypermethylated in cancer 1)
• BRCA1
• FHIT (fragile histidine triad)

Candidate tumor suppressor genes not frequently mutated but silenced by promoter hypermethylation include those for:

• O6-methylguanine-DNA methyltransferase (MGMT)
• cyclin dependent kinase inhibitor 2B (CDKN2B)
• RASSF1A

VHL, BRCA1 and serine-threonine kinase 11 (STK11) genes are often epigenetically silenced in sporadic forms of renal, breast and colon cancer respectively.

Hypermethylation can also predispose to mutational events during tumor progression. For example the DNA mismatch repair gene MLH1 is frequently hypermethylated in sporadic tumors that have microsatellite instability.

Tumor suppressor genes that are disrupted epigenetically often are in genomic regions with high frequency of chromosomal deletions.

In addition 5-methylcytosine can undergo spontaneous hydrolytic deamination to cause C -> T change.

More general terms

• DNA methylation (promoter methylation)