8 - epigenome and cancer

Question 1

genetic basis of cancer

Answer 1

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

Question 2

epigenetic basis of cancer

Answer 2

gene inactivation is as common as traditional cancerous mutation events

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

Question 3

epigenetic cancer research 1990s

Answer 3

researched DNA methylation abnormalities

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

Question 4

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

Answer 4

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

Question 5

how do epigenetic alterations cause cancer

Answer 5

mutations in chromatin-remodelling complexes

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

Question 6

example of mutations in haematopoietic malignancies

Answer 6

DNMT3A

TET2

Question 7

how does DNA hypermutation lead to cancer

Answer 7

causes promotor silencing

Question 8

how does DNA hypomethylation lead to cancer

Answer 8

causes genomic instability

Question 9

how does deamination lead to cancer

Answer 9

causes methylated CpG (meCpG)
–> causes gene silencing

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

G-T = mismatched base pairing

Question 10

methylation in oncogenesis

Answer 10

methylation can be gained or loss simultaneously to oncogenesis

Question 11

where do tumour cells hypermethylation

Answer 11

CpG island hot spots in promotor regions

Question 12

result of de novo promotor hypermethylation

Answer 12

leads to silencing of tumour suppressor genes

Question 13

result of de novo promotor hypomethylation

Answer 13

leads to activation of proto-oncogenes

Question 14

TSG

Answer 14

tumour suppressor gene

Question 15

MLH1

Answer 15

tumour suppressor gene involved in mismatch DNA repair

often mutated in colon cancer

Question 16

how does MLH1 cause colon cancer

Answer 16

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

Question 17

AML

Answer 17

Acute Myeloid Leukemia

most common type of leukemia in adults
heterogenous malignancy

Question 18

genetic mutations seen in AML patients

Answer 18

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

Question 19

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

Answer 19

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

Question 20

result of AR activation

Answer 20

transcriptional regulation of target genes

increased cellular proliferation/reduced apoptosis

Question 21

epigenetic alterations of AR in cancer

Answer 21

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

enhances growth pathways that bypass the need for AR

Question 22

other mechanisms affected by metastasis of prostate cancer cells

Answer 22

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

Question 23

CIMP

Answer 23

CpG Island Methylator Phenotype

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

Question 24

examples of CIMP-associated cancers

Answer 24

prostate
glioma
leukemia
breast

Question 25

stages of tumour progression in related to epigenetics

Answer 25

hyperplasia --> decreased 5hmc levels neoplasia --> increased CpG island methylation, altered histone modiifcation invasion --> high CpG island methylation, high altered histone modification levels

Question 26

hyperplasia

Answer 26

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

Question 27

neoplasia

Answer 27

formation of new, abnormal growth of tissue

Question 28

epigenetic characteristics of normal tissue

Answer 28

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

Question 29

which stage of tumour development would be a good therapeutic target

Answer 29

neoplasia increased CpG island methylation increased altered histone modification levels

Question 30

why is DNA methylation a good cancer biomarker

Answer 30

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

Question 31

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

Answer 31

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

Question 32

Detection of cancer in cell free circulating DNA (circDNA)

Answer 32

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

Question 33

active investigation of circDNA for clinical applications

Answer 33

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

Question 34

function of non-coding RNAs in cancer

Answer 34

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

Question 35

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

Answer 35

- miRNA, T-UCR and lincRNA profiling | - allows accurate differentiation between normal and cancerous tissue types

Question 36

hard’ alterations of DNA sequence

Answer 36

irreversible - mutations

Question 37

'soft’ adaptations of the chromatin template

Answer 37

reversible (modifications)

Question 38

new area of focus for epigenetic therapy

Answer 38

manipulation and resetting of the cancer epigenome targeting the epigenome using small molecules: - DNA hypomethylation agents (DNMTi) - Histone deacetylase (HDAC) inhibitors