Epigenetic Deregulation In Cancer Flashcards
Why might epigenetics be useful in cancer clincially
Can use cancer as diagnostic markers
Can use epigenetic patterns to identify ‘cancer genes’
Possible Targets for therapy
Could reactivate epigenetically silenced genes
Could inhibit onocogenes
What is commonly mutated in familial melanoma and breast cancer
p16
what is often epigenetically silenced in Burkitts lymphoma
p15 & p16
Describe the mutations often seen in Head and Neck Cancers
p15&p16 deleted in 67& of cases
epigenetically silenced in the other 25% of cases
Epigenetic changes in breast cancer
Hypermethylation of CHD1 gene
Also Hoxa5 hypremethylatied –> hence less p53 function as well
Describe epigenetic changes in glioblastomas
MGMT hypermethylation often occurs
MGMT hypermethylayion is actually a positive prognostic mark for a positive response to therapy
What is often epigenetically silenced in colorectal cancer
hMLH1 a mismatch repair gene
Describe what miRNA is often silenced in bladder cancer
miR127
How can we reactivate miR127 in bladder cancer
We can use:
AZA - a methylation inhibitor
PBA - a HDACi
What are the effects of reactivating miR127
miR127 can suppress the bcl6 protooncogene
However these treatments have genome wide effects, reactviating miR127 will also target other proteins as miRNAs can target many genes
What is often methylated in wilms tumours
Methylation at 5q31 –> these region contains over 50 genes that code for proto-cadherin genes
Also hypermethylated in breast and colorectal cancers
Give an example of long range epigenetic silencing shutting down whole regions
There is regional shut down of chromosome 2 in colorectal cancer
Describe the mutations and the epigenetic changes that are often seen in the WNt/B-catenin pathway
Wilms: Loss of WTX and CRC: Loss of APC –> both are components of the destruction complex
Get epigenetic silencing of SFRP in breast, glioma and CRC
Also get K3K27me3 of DACT3 –> which is a beta catenin agonist in CRC
Describe the epigenetic abnormalities that are often seen in neuroblastoma
Epigenetic silencing of NSD1 (a lysine methyltransferase) –> get promoter hypermethylation, you get a decrease in H3K4methylation and get overexpression of the MEIS1 onocogene
THIS IS EPIGENETIC REGULATION OF AN EPIGENETIC REGULATOR
What syndrome is NSD1 mutations associated with and describe the symptoms of the syndrome
SOTOS Syndrome
Macrocephaly, tall statue, overgrowth
Describe the epigenetic - genetic interaction that also occurs in neuroblastoma
Often get MYCN overexpression in neuroblastoma –> mycn upregulates Bmi1 oncogene –> this Bmi1 is part of the PRC1 complex and can suppress the TSGs TSLC1 and KIFBbeta
List the 3 glioma mutations leading to altered histones/genes
H3.3 - K27M mutation
H3.3. - G34R mutation
IDH1 - R132H mutation
Describe the H3.3 K27M mutation in glioblastoma
Get hypomethylation
Unique to childhood cancers
K27 may sequester EZH2 or EZH2 may be unable to methylate DNA –> this means that OLG2 isnt repressed. OLIG2 can intefere with p53 function
Describe the H3.3 G34R mutation in glioblastoma
Get hypomethylation
Unique to childhood gliomas
Targets the SETD2 methylation
Get H3.3 K26me3
Describe the IDH1 R132H mutation in glioblastoma
Get hypermethylation
Targets the TET enzyme
Mainly in adult gliomas
Get increased H3K9me3 and H3K27me3
What is the mechanism of the IDH1 R132H mutation in glioblastoma
Isocitrate converted to alpha-ketoglutarate –> mutant enzyme converts it D-2-hyperglutarate!!
Hence TET2 cant cause demethylation
Describe the mutations in Hereditary Diffuse Gastric Carcinoma
CHD1 often germline mutated
Often eften epigenetically silenced in the other allele
Describe an epigenetic marker that can be used to detect disease
Abherrant mehtylation of p16 and/or O16-methylguanosine can be detected in the sputum of 100% of squamous cell lung cancer patients up to 3 years before clinical diagnosis
How does bisulphite sequencing work
Converts C–> U however methylated cysteines can be deaminated
Describe the potential of an epigenetic therapy targeting non-Hodgkins Lymphoma
An oral EZH2 inhibitor has been shown to reguce tumour volume by decreasing histone methylation
What are bromodomain proteins
Ther are readers that recogenise epigenetic marks and can cause a chain of events
What bromodomain protein is involved with PRC2
BRD4
what is the role of BRD4 in cancer
Can super enhance some genes –> hence inhibitor of BET can decrease transcription
Name a gene that BRD4 cna superenahnce in cancer
c-myc
What gene is often hypermethylated in prostate cancer and can help with diagnosis
GSTP1 gene is hypermethylated in upto 90% Of prostate cancer but NOT in BPH
What is the prognosis of NSD1 methylation in neuroblastoma
Converys a poor prognosis
How can epigenetic alterations help explain response to treatment
When there is a lack of effectiveness of drugs e.g. tamoxifen in human related canceres may be due to epigenetic silencing of their receptors
Describe the genetic and epigenetic mutations often seen in colon cancer
genetic: p16, mLH1, Wnt/Beta - catenin, TGFB2R
epigenetic: At least 14 epigenetically silenced genes including WTCDKNA2, WT mLH1, SFRP
How can SFRP1 modulate Wnt activtiy
at low doses of Wnt it can potentiate Wnt singlaling
At higher concs of Wnt it can inhibit Wnt Signalling
What epigenetic changes may predispose early changes of tumourigenes
I.e. CDKNA2 methylation may allow mammary epitheliail cells to escape sensecence
What evidence is there that epigenetic pathways may mutate first
I.e. Abnormal methylation of SFRP seen in aberrant crpyt foci –> this may allow Wnt activation throguh epigenetics which can then acquire further mutations to upregulate Wnt
It may be these epigenetic changes are needed for the cloncal expansion and tumour progression: as deletion of the DNMT that inhibit SFRPs lead to apoptosis even with active beta-catenin. Also reexpression of SFRPs can block Wnt Signalling
