Week 13 - Cancer Genetics

Question 1

What is Cancer?

Answer 1

A disease caused by an uncontrolled division of abnormal cells in a part of the body

Question 2

Types of Tumors

Answer 2

Benign - a mass of cells that lacks the ability to invade neighbouring tissue or metastasize
Malignant - invades surrounding tissues and is usually capable of producing metastasis

Question 3

Requirements of a Cancer Cell

Answer 3

Sustain proliferative signalling
Evade growth suppressors 
Avoid immune destruction 
Enable replicative immortality 
Tumor-promoting inflammation
Activating invasion
Inducing angiogenesis
Genome instability and mutation
Resisting cell death
Deregulating cellular energetics

Question 4

Oncogene

Answer 4

Mutated and/or overexpressed version of a normal gene (proto-oncogene) that when dominant can release cell from normal restraints of growth
This with other changes converts cell into tumor cell

Question 5

Internal and External Factors that cause Cancer

Answer 5

Internal 
- faults in DNA repair mechanisms
- inherited mutations
- epigenetic factors
External 
- chemical mutagens
- radiation 
- infection e.g. virus

Question 6

Proto-oncogene

Answer 6

Normal genes that are present in normal cells that are involved in normal growth and development

Question 7

Retroviral Life Cycle

Answer 7

Enveloped ss RNA virus
Goes through reverse transcription making viral cDNA
Integrated into genome
Transcription and translation
Produces viral RNA and along with protein synthesis makes more viral RNA

Question 8

How does an oncogene in a retroviral genome differ from proto-oncogene?

Answer 8

Viral oncogene transcribed under control of viral promoter

Therefore oncogenes expressed at higher levels than proto-oncogene and sometimes transcribed in inappropriate cell types

Question 9

RNA Tumor Viruses

Answer 9

Retroviruses
Replicate via DNA intermediate 
Normal retrovirus consists of:
- duplicate RNA genomes
- icosahedral viral core
- envelope made from host cell membrane and viral glycoproteins

Question 10

Ways that RNA Tumor Viruses cause cancer

Answer 10

1. Some RNA tumor viruses have an extra gene in their genome
   - this viral gene is the transforming factor that causes infected cells to become cancerous
2. Cis-acting retroviruses
   - transformation caused by random integration into host gene such that LTR in close proximity to growth regulating genes
   - cause endogenous cellular gene to be overexpressed
   - leads to loss of control of cell proliferation
   - take longer to develop transducing viruses
3. Trans-acting retroviruses
   - cause up-regulation of cellular proto-oncogenes through action of viral transcription
   - long latency period between infection and tumor development

Question 11

DNA Tumor Viruses

Answer 11

DNA genome
Normally DNA viruses:
- enter host cell and produce protein that activates host transcription
- use host protein to replicate genome and create large number of progeny virus
- lyse the cell releasing new virus particles
Sometimes viral DNA becomes integrated into cell before its replicated and viral proteins expressed
These viral proteins interact with host proteins preventing host protein from functioning correctly

Question 12

SV40

Answer 12

DNA tumor virus
Large T antigen - inactivates cell cycle arrest genes and inhibits programmed cell death
Binds RB and p53
Therefore SV40 proteins inactivate cellular tumor suppressors

Question 13

Cervical Cancer

Answer 13

Abnormal cell growth on cervix
Caused by HPV infection
Pre-cancerous changes long before invasive cancer develops

Question 14

Gardasil

Answer 14

Protects against types of HPV
Prevents infection; doesn't treat existing infection
Highly effective
Side effects
- fatigue
- paralysis
- blindness

Question 15

How do proto-oncogenes become oncogenes?

Answer 15

Through number of mutations anywhere on a signalling pathway
Growth factors
- become activated by transcriptional activation of gene leading to overproduction
Growth factor receptors
- become constitutively activated
Signal transducers
- become constitutively activated
Transcription factors
- deregulation
Regulators of cell death

Question 16

RAS Oncogene

Answer 16

Super family of membrane associated G-coupled proteins
Participate in proliferation, motility and survival
When mutated they lead to deregulated cell proliferation, survival, invasion and angiogenesis
Mutations occur at codon 12
Proto-oncogenic form of RAS - GGC to Gly
Oncogenic form of RAS - GTC to Val

Question 17

Guanine Nucleotide Exchange Factors (GEFs)

Answer 17

Proteins that activate monomeric GTPases by stimulating release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP)

Question 18

Tumor Suppressor Genes

Answer 18

Prevent cells with mutations from becoming cancers by causing them to stop proliferating
Allows DNA repair mechanisms to fix the mutated DNA
or by inducing them to commit suicide if the damage is too great
Inactivation of TSGs leads to cancer
Inactivation of TSGs is a loss of function mutation - recessive

Question 19

p53 Tumor Suppressor Gene

Answer 19

p 53 protein produced by p53 gene
It inhibits cell proliferation and transformation
Activated in response to multiple cellular stresses
In normal cells the level of p53 is low and is regulated by MDM2
Attachment of MDM2 to p53 leads to destruction of p53 in the cell

Question 20

Inactivation of p53

Answer 20

Feature of more than 50% of all human cancers

Can be caused by point mutations which can inhibit p53 from binding to transcription factor binding sites on DNA

Question 21

RB Tumor Suppressor Gene

Answer 21

Normal RB protein (pRB) switches from active to inactive
depending on the stage in the cell-cycle
Controls availability of the E2F transcription factor in G1 to S checkpoint
With no RB, E2F produces protein which helps development of cancer cells
Mutations anywhere in the RB gene lead to inability to downregulate these transcription factors
Leads to transcription at wrong times

Question 22

Apoptosis

Answer 22

Programmed cell death
Fundamental cell process involved in:
- development 
- maintenance of tissue homeostasis 
- elimination of damaged cells 
Two pathways leading to this:
1. Extrinsic 
- death receptors on outside of cell are activated 
2. Intrinsic 
- mitochondria releases Cytochrome C in response to stress signals
Both pathways lead to activation of a series of enzymes called caspases
Caspases are cysteine proteases

Question 23

What happens when Apoptosis goes wrong?

Answer 23

Can cause:
- neurodegenerative disease
- diabetes 
- cancer
Apoptosis can be blocked by both oncogenes and faulty tumor suppressor genes