Lecture 24: Cancer Epigenetics Flashcards
What are the two epigenetic mechanisms
- DNA Methylation - covalent mod of -CH3 to CpG dinucleotides
- Histone modifications - Various post-trans modifications
What is DNA methylation?
addition of a methyl group to cytosine bases of CpG dinucleotides
Which enzymes add methylation to DNA
- DNMT3 A and B (de novo)
- DNMT1 maintenance during replication
Which enzymes r moveemethylation to DNA
TET1-3
Where can DNA methylatoin be found?
Gene bodies (not promoters) highly methylated to stop spurious transcription initiation and production of potentially deleterious transcription or truncated proteins
LINE-1, Alu-repeats, HERVs are silenced by methylation to prevent them jumping around the genome
How is methylation linked to cancer?
Hyper-methylated tumour suppressor genes
Hypomethylated: oncogenes, genome wide methylation -> chromosomal instability
What is an example of DNA methylation in cancer?
Hypermethylation of RB1 gene in retinoblastoma (first reported hypermethylated cancer)
Epigenetic silencing is mutually exclusive to structural or mutational inactivation of the same gene, highlighted for BRCA1 and CDKN2A in ovarian cancer
How is the CpG island methylator phenotype (CIMP) seen in colorectal carcinogenesis?
Some colorectal cancers presented with concordant tumour-specific DNA methylation throughout the genome suggested the existence of systemic methylaion defect
This was refered to as the CIMP
These findings suggest that hypermethylation of specific gene panels associated with the CIMP phenotype in a specific tumour type could have prognostic predictive value
CIMP-high cancer primarily in older patients - hence age-related hypermethylated ay play a role
Methylation is critical in progression of invasive cancer, primarily due to silencing of the mis-match repair gene MLH1
How is CIMP seen in gliomas?
Mutant IDH protein produces the oncometabolite D-2-hydroxyglutarate (2HG) which may establish the glioma-CIMP
The TET family are directly responsible for generation of 5hmC, and the catalytic reaction requires the cofactor 2HG which is mainly controlled by isocitrate dehydrogenases (IDHs)
How is Aberrant DNA methylation being used for a marker for disease?
Early detection can result in improved clinical outcomes:
e.g., GSTP1 hypermethylation in prostate cancer
Prediction of drug sensitivity, e.g., hypermethylation of MGMT clinical biomarker for chemo sensitivity to temozolomide in gliomas
How can cfDNA be used for cancer detection?
Tumours release a substantial amount of genomic DNA into biological fluids
What is 5-aza CR?
DNA Methylation drug.
High doses of 5-aza-cytidine and 5-aza-2’-deoxycytidine is cultured in tummour cells reactivate key TSG functino lost during tumour progression
Once incorporated into DNA, it covalently traps DNMTs, ultimately inhibiting DNA methylation in subsequent rounds of synthesis
Initial doses were too toxic to patients, however, now used in treatment of certain heamatological malignancies - e.g., myelodysplastic syndrome
