Cancer

Question 1

Name 3 differences between cancerous and non-cancerous cells?

Answer 1

Cancerous - abnormal morphology, dysregulated growth, loss of contact inhibition
Non-cancerous cells, standard morphology, organised monolayer, have contact inhibition

Question 2

What is a proto-oncogene and what are its main roles?

Answer 2

It is a normal cellular gene. It codes for ‘oncoprotein’ that are
important for stimulating cell growth and differentiation!!!
- regulates transcription
- growth factor signalling
- INHIBITS APOPTOSIS

Question 3

When proto-oncogenes acquire mutations they are called? Give some examples

Answer 3

Oncogenes

• Cytokine/growth factor: e.g. EGFR
• Transcription factor: Myc
• Signalling kinase: Src
• anti-apoptotic factors - Bcl

Question 4

In what ways can protooncogenes acquire mutations?

Answer 4

1. Gain of function mutations: when very specific mutations are involved
2. Dominant effect: only one copy of the gene needs to be mutated to elicit and effect

Question 5

Name some some specific mutational mechanisms of proto-oncogenes

Answer 5

Point mutations e.g. KRAS
Amplification e.g. N-MYC
Translocation e.g. BcR-AbL

Question 6

What is KRAS? What is its role in normal cell function? What happens when it is mutated?

Answer 6

KRAS - member of the RAS family, type of proto-oncogene
- important for normal proliferation, differentiation, senescence
In GTP - bound state: ACTIVE: signals growth and inhibition of apoptosis
In GDP - bound state: INACTIVE:

KRAS mutations, are dominant point mutations.
It causes KRAS to be stuck in the GTP bound state by blocking the intrinsic GTP activity.

Question 7

What is N-MyC? What is its role in normal cell function? What happens when it is mutated?

Answer 7

N-MyC, proto-oncogene. It is a transcription factor. Primarily expressed in EMBRYOS. - Critical in brain and neural development.
- promotes division of neuron progenitors

When it is mutated: It is amplified/over-expressed and can cause neuroblastoma.

Question 8

What is Bcr and Abl involved in during normal cell function?

Answer 8

ABL - it is a tyrosine kinase, involved in differentiation, division, adhesion
BCR - serine/thereonine kinase, involved in cell signalling

Question 9

What happens during Bcr-Abl translocation?

Answer 9

The Bcr and Abl gene fuse together on chromosome 22 ‘Philadelphia chromosome’.

• It dysregulates the tyrosine kinase function
• acts as active growth hormone receptor ===> driving myeloid proliferation

FOUND IN CHRONIC MYELOID LEUKEMIA (CML)

Question 10

How can you therapeutically target BcR-Abl translocation?

Answer 10

a) inhibits the tyrosine kinase activity

b) Imatinib mesylate - binds competitively to bcr-abl and inhibits the protein

Question 11

What is a tumour suppressor gene (TSG)? Give some examples

Answer 11

TSGs STOP cell growth, THEY KEEP THE CELL IN CHECK. Activate apoptosis, block cell cycle from continuing, respond to damaged DNA.

• cell cycle regulation e.g. RB1
• DNA damage checkpoints and apoptosis e.g. TP53 (p53)
• cell adhesion signalling e.g. APC
• DNA Repair e.g. BRCA1

Question 12

What type of mutations do tumour suppressor genes acquire?

Answer 12

Loss of function mutations: many different types of mutations are involved
and Recessive effect: both versions of the gene need to be mutated

OFTEN IN FAMILIAL CANCERS

Question 13

Name some some specific mutational mechanisms that inactivate tumour suppressor genes

Answer 13

point mutations e.g. change a codon
deletion/insertion
inversions
methylation

however remember it requires both genes to be inactive to cause uncontrolled growth

Question 14

What is a Loss of Hetrerozygosity (LOH)?

Answer 14

Generally occurs in TSG mutations.

A POINT mutation in one allele followed by DELETION of the other allele.

Question 15

RB1 is a type of TSG, what kind disorder can it cause?

Answer 15

Retinoblastoma
cancerous tumour of the retina
bilateral - if it is an inherited mutation
unilateral - if it is a sporadic mutation

Question 16

What is p53? why is it important? what happens when it is mutated?

Answer 16

p53 is the “gatekeeper” of tumour suppressor gene
It is:
a) transcription factor
b) cell cycle check point protein (G1 to S phase -do we want to replicate the DNA?)
c) DNA damage mediated apoptosis

If a person only inherits one functional copy of the p53 gene, and the other one has an inactivated mutation - the normal copy will be lost ==> can develop Li-Fraumeni syndrome in adulthood

Question 17

Explain the difference between sporadic (acquired) vs inherited (familial) cancer

Answer 17

Sporadic - occurs in the somatic cell

• mutations dont often happen in the genes but they occur all the time in cells
• takes a long time to happen
• generally have a later onset in life

Inherited - occurs in the germ line cell

• if its the TSG that has the mutation, the second copy of the gene will quickly get the mutation also
• activated mutations of oncogenes are usually embroyanically lethal so its not usually inherited
• early onset, usually TSGs

Question 18

How do viruses cause cancer?

Answer 18

Viruses can cause cancer by acting as oncogenes.
They insert viral oncogenic genes into the host cell, affect the existing porto-oncogenes and block the function of TSGs

e.g. human papilloma virus causing cervical cancer

Question 19

Explain underlying mechanisms in colon cancer

Answer 19

Normal epithelium — (LOSS OF APC gene) —–> Hyper proliferation of epithelium —> Early adenoma “benign tumour of the glandular epithelium” —– (ACTIVATION OF THE KRAS GENE) —-> Intermediate adenoma —- (LOSS OF THE DCC Gene/chromosome 22) —> late adenoma — (LOSS OF p53 gene) —-> Carcinoma — (OTHER ALTERATIONS) —-> Metastasis

Question 20

What are the colon risk factors (%) of familial vs sporadic?

Answer 20

20% familial

30% due to nutrition of high fats, meat, high BMI etc

Question 21

What are the 6 hallmarks of cancer?

Answer 21

• Proliferation signalling
• Cell Death resistance
• Angiogensis
• Metastisis/Invasion
• Replication immortality
• Evade from growth suppressors

Question 22

What is Familial adenomatous polyposis (FAP)? What is caused by?

Answer 22

Autosomal dominant, pre-malignant disease that usually progresses to malignancy. Causes innumerable polyps – CAUSED BY APC gene

Question 23

What is APC?

Answer 23

APC - adenomatous polyposis coli gene

• encodes a tumour suppressor protein
• The protein made by the APC gene plays a critical role in several cellular processes that determine whether a cell may develop into a tumor.
• inactivation of APC. When APC does not have an inactivating mutation, frequently there are activating mutations in beta catenin.
• Mutations in APC or β-catenin must be followed by other mutations to become cancerous; however, in carriers of an APC inactivating mutation

Question 24

What are stability genes?

Answer 24

• normally function to repair error of DNA replication or those cause by outages
• When they are inactivated, errors slowly accumulate
• produces expansions and contractions of micro satellite DNA sequences, tandem repeats of nucleotides leading to “micro satellite instability”

Question 25

What is hereditary non-polyposis (HNPCC) caused by?

Answer 25

inherited mutation of mismatch repair genes

in brown nuclear staining, MMR (mismatch repair) protein should be present