8 - epigenome and cancer Flashcards
genetic basis of cancer
cancer is caused by mutational changes to tumour suppressor genes or oncogenes
epigenetic basis of cancer
gene inactivation is as common as traditional cancerous mutation events
cancer is a disease of gene expression dysregulation –> allows cells to grow unchecked
epigenetic cancer research 1990s
researched DNA methylation abnormalities
discovered role of chromatin covalent modification and organisation and relevance to gene expression
what do we still need to learn more about the cancer epigenome
knowledge of how genetic and epigenetic alterations help drive the initiation/progression of cancer to help discover cancer biomarkers and therapeutic opportunities
how do epigenetic alterations cause cancer
mutations in chromatin-remodelling complexes
epigenetic regulatory mutations are advantageous to cancer cells –> rewire transcriptional programs
example of mutations in haematopoietic malignancies
DNMT3A
TET2
how does DNA hypermutation lead to cancer
causes promotor silencing
how does DNA hypomethylation lead to cancer
causes genomic instability
how does deamination lead to cancer
causes methylated CpG (meCpG)
–> causes gene silencing
5-methyl cytosine is unstable and mutates to thymine (TpG) –> cancer
G-T = mismatched base pairing
methylation in oncogenesis
methylation can be gained or loss simultaneously to oncogenesis
where do tumour cells hypermethylation
CpG island hot spots in promotor regions
result of de novo promotor hypermethylation
leads to silencing of tumour suppressor genes
result of de novo promotor hypomethylation
leads to activation of proto-oncogenes
TSG
tumour suppressor gene
MLH1
tumour suppressor gene involved in mismatch DNA repair
often mutated in colon cancer
how does MLH1 cause colon cancer
if the promotor region of MLH1 is hypermethylated, then the gene is silenced and cannot perform DNA repairs
AML
Acute Myeloid Leukemia
most common type of leukemia in adults
heterogenous malignancy
genetic mutations seen in AML patients
DNMT3A mutations TET2 mutations (associated with reduced levels of 5hmc)
method of activation of the androgen receptor (AR) in prostate cancer
conversion of testosterone to potent dihydrotestosterone (DHT) triggers AR activation
result of AR activation
transcriptional regulation of target genes
increased cellular proliferation/reduced apoptosis
epigenetic alterations of AR in cancer
hypermethylation-associated AR inactivation in hormone-refractory prostate cancer cells
enhances growth pathways that bypass the need for AR
other mechanisms affected by metastasis of prostate cancer cells
- cell adhesion proteins abrogated by promotor hypermethylation
- loss of cell-cycle regulators allows uncontrolled proliferation
- promoter methylation promotes genome damage
CIMP
CpG Island Methylator Phenotype
important for gene inactivation is cancer cells–> important cellular pathways become inactivated
examples of CIMP-associated cancers
prostate
glioma
leukemia
breast
stages of tumour progression in related to epigenetics
hyperplasia –> decreased 5hmc levels
neoplasia –> increased CpG island methylation, altered histone modiifcation
invasion –> high CpG island methylation, high altered histone modification levels
hyperplasia
enlargement of tissue due to increase in reproduction rate of cells
–> initial stage in cancer development
neoplasia
formation of new, abnormal growth of tissue
epigenetic characteristics of normal tissue
high 5hmc levels
low CPG island methylation
low altered histone modification levels
which stage of tumour development would be a good therapeutic target
neoplasia
increased CpG island methylation
increased altered histone modification levels
why is DNA methylation a good cancer biomarker
- common event in carcinogenesis
- easy to detect
- high sensitivity and specificity (90%)
- DNA methylation more stable that RNA or protein based biomarkers
- non-invasice
where do you detect DNA methylation as a biomarker in cancer examples
lung cancer -> plasma
prostate cancer –> urine, blood, ejaculate
colon –> blood
Detection of cancer in cell free circulating DNA (circDNA)
circDNA is released from the tumour into the blood
allows identification of cancer cell alterations such as DNA mutations and methylation
useful for basis of blood-based diagnostic test
active investigation of circDNA for clinical applications
e.g. blood test for colorectal cancer based on methylation of SEPT9 promoter region in circDNA
function of non-coding RNAs in cancer
changes in miRNA expression causes neoplasia
can downregulate important genes e.g. HOX
miRNA variation affects cancer susceptibility
epi-miRNAs control epigenetic machinery e.g. DNA methyl transferases
use of non-coding RNA as a diagnostic tool for cancer
- miRNA, T-UCR and lincRNA profiling
- allows accurate differentiation between normal and cancerous tissue types
hard’ alterations of DNA sequence
irreversible - mutations
‘soft’ adaptations of the chromatin template
reversible (modifications)
new area of focus for epigenetic therapy
manipulation and resetting of the cancer epigenome
targeting the epigenome using small molecules:
- DNA hypomethylation agents (DNMTi)
- Histone deacetylase (HDAC) inhibitors
