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Developmental Genetics and Embryonal Cancers > Epigenetic Deregulation In Cancer > Flashcards

Epigenetic Deregulation In Cancer Flashcards

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1
Q

Why might epigenetics be useful in cancer clincially

A

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

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2
Q

What is commonly mutated in familial melanoma and breast cancer

A

p16

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3
Q

what is often epigenetically silenced in Burkitts lymphoma

A

p15 & p16

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4
Q

Describe the mutations often seen in Head and Neck Cancers

A

p15&p16 deleted in 67& of cases

epigenetically silenced in the other 25% of cases

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5
Q

Epigenetic changes in breast cancer

A

Hypermethylation of CHD1 gene

Also Hoxa5 hypremethylatied –> hence less p53 function as well

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6
Q

Describe epigenetic changes in glioblastomas

A

MGMT hypermethylation often occurs

MGMT hypermethylayion is actually a positive prognostic mark for a positive response to therapy

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7
Q

What is often epigenetically silenced in colorectal cancer

A

hMLH1 a mismatch repair gene

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8
Q

Describe what miRNA is often silenced in bladder cancer

A

miR127

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9
Q

How can we reactivate miR127 in bladder cancer

A

We can use:
AZA - a methylation inhibitor
PBA - a HDACi

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10
Q

What are the effects of reactivating miR127

A

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

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11
Q

What is often methylated in wilms tumours

A

Methylation at 5q31 –> these region contains over 50 genes that code for proto-cadherin genes

Also hypermethylated in breast and colorectal cancers

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12
Q

Give an example of long range epigenetic silencing shutting down whole regions

A

There is regional shut down of chromosome 2 in colorectal cancer

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13
Q

Describe the mutations and the epigenetic changes that are often seen in the WNt/B-catenin pathway

A

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

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14
Q

Describe the epigenetic abnormalities that are often seen in neuroblastoma

A

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

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15
Q

What syndrome is NSD1 mutations associated with and describe the symptoms of the syndrome

A

SOTOS Syndrome

Macrocephaly, tall statue, overgrowth

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16
Q

Describe the epigenetic - genetic interaction that also occurs in neuroblastoma

A

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

17
Q

List the 3 glioma mutations leading to altered histones/genes

A

H3.3 - K27M mutation
H3.3. - G34R mutation
IDH1 - R132H mutation

18
Q

Describe the H3.3 K27M mutation in glioblastoma

A

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

19
Q

Describe the H3.3 G34R mutation in glioblastoma

A

Get hypomethylation
Unique to childhood gliomas
Targets the SETD2 methylation
Get H3.3 K26me3

20
Q

Describe the IDH1 R132H mutation in glioblastoma

A

Get hypermethylation
Targets the TET enzyme
Mainly in adult gliomas
Get increased H3K9me3 and H3K27me3

21
Q

What is the mechanism of the IDH1 R132H mutation in glioblastoma

A

Isocitrate converted to alpha-ketoglutarate –> mutant enzyme converts it D-2-hyperglutarate!!

Hence TET2 cant cause demethylation

22
Q

Describe the mutations in Hereditary Diffuse Gastric Carcinoma

A

CHD1 often germline mutated

Often eften epigenetically silenced in the other allele

23
Q

Describe an epigenetic marker that can be used to detect disease

A

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

24
Q

How does bisulphite sequencing work

A

Converts C–> U however methylated cysteines can be deaminated

25
Q

Describe the potential of an epigenetic therapy targeting non-Hodgkins Lymphoma

A

An oral EZH2 inhibitor has been shown to reguce tumour volume by decreasing histone methylation

26
Q

What are bromodomain proteins

A

Ther are readers that recogenise epigenetic marks and can cause a chain of events

27
Q

What bromodomain protein is involved with PRC2

A

BRD4

28
Q

what is the role of BRD4 in cancer

A

Can super enhance some genes –> hence inhibitor of BET can decrease transcription

29
Q

Name a gene that BRD4 cna superenahnce in cancer

A

c-myc

30
Q

What gene is often hypermethylated in prostate cancer and can help with diagnosis

A

GSTP1 gene is hypermethylated in upto 90% Of prostate cancer but NOT in BPH

31
Q

What is the prognosis of NSD1 methylation in neuroblastoma

A

Converys a poor prognosis

32
Q

How can epigenetic alterations help explain response to treatment

A

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

33
Q

Describe the genetic and epigenetic mutations often seen in colon cancer

A

genetic: p16, mLH1, Wnt/Beta - catenin, TGFB2R
epigenetic: At least 14 epigenetically silenced genes including WTCDKNA2, WT mLH1, SFRP

34
Q

How can SFRP1 modulate Wnt activtiy

A

at low doses of Wnt it can potentiate Wnt singlaling

At higher concs of Wnt it can inhibit Wnt Signalling

35
Q

What epigenetic changes may predispose early changes of tumourigenes

A

I.e. CDKNA2 methylation may allow mammary epitheliail cells to escape sensecence

36
Q

What evidence is there that epigenetic pathways may mutate first

A

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

Developmental Genetics and Embryonal Cancers (18 decks)

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