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TMS exam > 8 - epigenome and cancer > Flashcards

8 - epigenome and cancer Flashcards

1
Q

genetic basis of cancer

A

cancer is caused by mutational changes to tumour suppressor genes or oncogenes

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2
Q

epigenetic basis of cancer

A

gene inactivation is as common as traditional cancerous mutation events

cancer is a disease of gene expression dysregulation –> allows cells to grow unchecked

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3
Q

epigenetic cancer research 1990s

A

researched DNA methylation abnormalities

discovered role of chromatin covalent modification and organisation and relevance to gene expression

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4
Q

what do we still need to learn more about the cancer epigenome

A

knowledge of how genetic and epigenetic alterations help drive the initiation/progression of cancer to help discover cancer biomarkers and therapeutic opportunities

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5
Q

how do epigenetic alterations cause cancer

A

mutations in chromatin-remodelling complexes

epigenetic regulatory mutations are advantageous to cancer cells –> rewire transcriptional programs

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6
Q

example of mutations in haematopoietic malignancies

A

DNMT3A

TET2

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7
Q

how does DNA hypermutation lead to cancer

A

causes promotor silencing

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8
Q

how does DNA hypomethylation lead to cancer

A

causes genomic instability

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9
Q

how does deamination lead to cancer

A

causes methylated CpG (meCpG)
–> causes gene silencing

5-methyl cytosine is unstable and mutates to thymine (TpG) –> cancer

G-T = mismatched base pairing

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10
Q

methylation in oncogenesis

A

methylation can be gained or loss simultaneously to oncogenesis

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11
Q

where do tumour cells hypermethylation

A

CpG island hot spots in promotor regions

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12
Q

result of de novo promotor hypermethylation

A

leads to silencing of tumour suppressor genes

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13
Q

result of de novo promotor hypomethylation

A

leads to activation of proto-oncogenes

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14
Q

TSG

A

tumour suppressor gene

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15
Q

MLH1

A

tumour suppressor gene involved in mismatch DNA repair

often mutated in colon cancer

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16
Q

how does MLH1 cause colon cancer

A

if the promotor region of MLH1 is hypermethylated, then the gene is silenced and cannot perform DNA repairs

17
Q

AML

A

Acute Myeloid Leukemia

most common type of leukemia in adults
heterogenous malignancy

18
Q

genetic mutations seen in AML patients

A 
DNMT3A mutations 
TET2 mutations (associated with reduced levels of 5hmc)
19
Q

method of activation of the androgen receptor (AR) in prostate cancer

A

conversion of testosterone to potent dihydrotestosterone (DHT) triggers AR activation

20
Q

result of AR activation

A

transcriptional regulation of target genes

increased cellular proliferation/reduced apoptosis

21
Q

epigenetic alterations of AR in cancer

A

hypermethylation-associated AR inactivation in hormone-refractory prostate cancer cells

enhances growth pathways that bypass the need for AR

22
Q

other mechanisms affected by metastasis of prostate cancer cells

A
  • cell adhesion proteins abrogated by promotor hypermethylation
  • loss of cell-cycle regulators allows uncontrolled proliferation
  • promoter methylation promotes genome damage
23
Q

CIMP

A

CpG Island Methylator Phenotype

important for gene inactivation is cancer cells–> important cellular pathways become inactivated

24
Q

examples of CIMP-associated cancers

A

prostate
glioma
leukemia
breast

25
Q

stages of tumour progression in related to epigenetics

A

hyperplasia –> decreased 5hmc levels

neoplasia –> increased CpG island methylation, altered histone modiifcation

invasion –> high CpG island methylation, high altered histone modification levels

26
Q

hyperplasia

A

enlargement of tissue due to increase in reproduction rate of cells
–> initial stage in cancer development

27
Q

neoplasia

A

formation of new, abnormal growth of tissue

28
Q

epigenetic characteristics of normal tissue

A

high 5hmc levels
low CPG island methylation
low altered histone modification levels

29
Q

which stage of tumour development would be a good therapeutic target

A

neoplasia

increased CpG island methylation
increased altered histone modification levels

30
Q

why is DNA methylation a good cancer biomarker

A
  • common event in carcinogenesis
  • easy to detect
  • high sensitivity and specificity (90%)
  • DNA methylation more stable that RNA or protein based biomarkers
  • non-invasice
31
Q

where do you detect DNA methylation as a biomarker in cancer examples

A

lung cancer -> plasma
prostate cancer –> urine, blood, ejaculate
colon –> blood

32
Q

Detection of cancer in cell free circulating DNA (circDNA)

A

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

33
Q

active investigation of circDNA for clinical applications

A

e.g. blood test for colorectal cancer based on methylation of SEPT9 promoter region in circDNA

34
Q

function of non-coding RNAs in cancer

A

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

35
Q

use of non-coding RNA as a diagnostic tool for cancer

A
  • miRNA, T-UCR and lincRNA profiling

- allows accurate differentiation between normal and cancerous tissue types

36
Q

hard’ alterations of DNA sequence

A

irreversible - mutations

37
Q

‘soft’ adaptations of the chromatin template

A

reversible (modifications)

38
Q

new area of focus for epigenetic therapy

A

manipulation and resetting of the cancer epigenome

targeting the epigenome using small molecules:

  • DNA hypomethylation agents (DNMTi)
  • Histone deacetylase (HDAC) inhibitors

TMS exam (22 decks)

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