Trigger 8: Epigenetics and cancers Flashcards
epigenetic-drven gene inactivation is at least as common as
mutational events which lead to cancers
understanding how genetic and epigenetic alteration drive the initiation nd progression of cancer
will help foster new potential cancer biomarkers and therapeutic opportunities
mutations in the epigenetic writers, readers and eraser
common in cancers
mutations in members of chromatin-remodelling complexes
common in cancer
mutations in the epigenetic regulators offer the cancer cell number of advantages
- require transcriptional programs
- adapt to environmental or therapeutic pressures
which epigenome enzyme are commonly mutated in hematopoietic malignancies
DNMT3A and TET2
DNA hypermethylation leads to
promotor silencing
DNA hypomethylation leads to
genomic instability
deamination of meCpG to TpG leads to
mutation
DNA hypermethylation and hypomethylation and deamination all lead to
cancer
DNA methylation plays a
critical role in carcinogenensis
global hypomethylation
increase genomic instability
de novo promoter hypermethylation leads to silencing of
tumour suppressing genes
de novo promoter hypomethylation may result in activation of
porto-oncogenes
hypermethylation and cancer effects
tumour suppressor genes
name a tumour suppressor gene which is frequently altered in cancers
MLH1
Epigenomics silencing of non-mutated MLH1 gene
mismatch repair protein- - frequently silenced by epigenetic in non-familial colon cancer
mutated epigenetic machinery in cancer (acute myeloid leukaemia (AML)
DNMT3A and TET2
Aberrant DNA methylation of multiple genes inc cancer related pathways
is a common event in carcinogenesis
cancers can be classified according to
their degree of methylation
CPG island methylator (CIMP) phenotype in cancer
= CIMP-associated cancers seem to have a distinct epidemiology, histology, and molecular features.
- The CIMP subtype has been documented in several additional cancers including prostate, glioma, leukaemia, and breast.
combination of …… and …. in the hall marks of cancer
epigenetic modification and mutation
screening for novel genes epigentially silenced inc ancer
identify novel cancer-related differentially methylated genes
validated using standard techniques such as QMSP and pyrosequencing
cancer can be detected by
assessing DNA methylation
DNA methylation has the potential to be an excellent cancer biomarker because
- DNA meth changes are common events in carcinogenesis
- easy to detect with high sensitivity
- DNAmeth is more stable than RNA or protein based markers
examples of cancers which can be detected by DNA methylation
- prostate
- lung cancer
- colon cancer
detection of cancer in cell free circulating DNA
molecular alterations found int tumour cells, such as methylation, is reflected in cell-free circulating DNA, released from tumour cell into the blood
CircDNA is
an ideal candidate for the basis of blood-based cancer diagnostic tests
prostate cancer gene
GSTP1
Lung cancer gene
SHOX2
colon cancer gene
Sept9
deactivated hitsone
closed chromatin- gene silencing
acetylation of histones
Abnormally open nucleosome configuration
name the most clinically advances epigenetic therapies in oncology
DNA hypomethylating agents (DNMTi)
Histone deactylase (HDAC) inhibitors
DNA methylation inhibition
lacks specificity
resistance is common
not very successful in solid tumours
HDAC inhibitors (HDACi) examples
Vorinostat
DNMTi and HDACi have their greatest efficacy when
combined with other cancer therapies
DNMTi is combined with
standard cytotoxic drugs in an attempt to resentisie cancer
epigenitcs can also be used with
immunotherapy
Cancer epigenetic research challenges
- how is heritable gene silencing in cancer cells maintained
- epigenetic biomarkers have low sensitivity and specificity
when epigenetic biomarkers lack specificity
adverse side effects and off target affects
