Molecular hallmarks of cancer cells

Question 1

What are caretaker genes?

Answer 1

Maintain genetic stability by repairing damaged DNA and replication errors. I.e. tumour suppressor genes when active

Question 2

What is a common feature of most tumour cells?

Answer 2

Genetic instability

Question 3

What are driver mutations?

Answer 3

Mutations in proto-oncogenes/tumour-suppressor genes that drive cancinogenesis.

Question 4

What are the two different types of tumour suppressor gene?

Answer 4

Gatekeepers and caretakers

Question 5

What are gatekeeper genes?

Answer 5

Play important roles in regulating normal growth:

• negative regulators of the cell cycle and proliferation
• positive regulators of apoptosis
• positive regulators of cell differentiation

Question 6

What are caretaker genes?

Answer 6

Maintain genetic stability

• DNA repair genes
• controlling accuracy of mitosis

Question 7

What sort of mutations are required of tumour suppressor genes for carcinogenics?

Answer 7

Loss of function - point mutations, deletions/insertions, chromosomal rearrangements, epigenetic silencing

Question 8

Do loss of function mutations contribute directly to the tumourigenic phenotype?

Answer 8

No - such mutations simply create the conditions whereby mutations have a chance to arise in gatekeeper TSGs.

Question 9

What kind of mutation usually provides the first hit for a TSG?

Answer 9

Point mutation in the coding sequence.

Question 10

What kind(s) of mutation provide the second hit for a TSG and why?

Answer 10

Chromosomal non-disjunction
Gene conversion
Mitotic recombination
Epigenetic inactivation through promotor methylation

These types of mutational events are 3x more common than point mutations.

Question 11

Which gene is involved in retinoblastoma?

Answer 11

Gene: RB1
Tumour: retinoblastoma

Question 12

What gene and principle tumours are involved in Li-Fraumeni?

Answer 12

Gene: p53
Tumour: sarcomas, breast

Question 13

What gene and principle tumour is involved in familial adenomatous polyposis?

Answer 13

Gene: APC
Tumour: colorectal

Question 14

What genes and principle tumours are involved in familial breast cancer?

Answer 14

Genes: BRCA1, BRCA2
Tumours: breast, ovarian

Question 15

What genes and principle tumours are involved in HNPCC?

Answer 15

Genes: hMLH1, hMSH2
Tumours: colon, endometrial

Question 16

What is typically inherited in familial cancer syndromes?

Answer 16

Mutant copy of gatekeeper or caretaker gene.

Question 17

What is the lifetime risk of a carrier developing cancer?

Answer 17

70-90% depending on the syndrome

Question 18

What are proto-oncogenes?

Answer 18

Genes that promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis.

Question 19

What are the features of oncogenes?

Answer 19

• Mutations lead to activated versions or increased expression of proto-oncogenes – GAIN OF FUNCTION.
• Cause increased levels of cell proliferation, survival, angiogenesis and inhibition of apoptosis.
• Only 1 copy of the gene needs to be activated to induce a gain of function. Mutated gene is dominant to the other normal parental gene.

Question 20

What are the mechanisms of oncogene activation?

Answer 20

Translocation
Point mutation
Amplification

Question 21

What is translocation?

Answer 21

Movement of a proto-oncogene from a low transcriptionally active site on a chomosome to an active site on the same/different chromosome - aberrant expression of the oncogene.

eg Burkitt’s lymphoma

Question 22

How does amplification work?

Answer 22

Insertion of multiple copies of an oncogene – increased expression

Question 23

What is the minimum number of genetic mutations required to transform a normal cell into a neoplastic cell?

Answer 23

3

Question 24

What are the hallmarks of cancer cells?

Answer 24

• Self-sufficiency in growth
• Insensitivity to antigrowth signals
• Tissue invasion and metastasis
• Limitless potential for replication
• Sustained angiogenesis
• Evading apoptosis

Question 25

What is 'self-sufficiency in growth factors'?

Answer 25

Independence from positive growth factors e.g. EGFR (receptor for TGF alpha)

Question 26

What is RAS?

Answer 26

Single subunit small GTPase indirectly coupled to EGFR (tyrosine kinase)

Question 27

What happens to RAS when it becomes an oncoprotein?

Answer 27

It loses its GTPase function - remains permanently active.

Question 28

What is the function of the retinoblastoma protein?

Answer 28

In quiescent cells the RB protein binds to and inactivates pro-growth factors. In proliferating cells the RB protein is deactivated by phosphorylation by kinases switched on via proliferation signal transduction pathway. Negative growth factors, such as TGFbeta, activate RB by stimulating the expression of proteins that inhibit kinases.

Question 29

How can cancer cells escape the inhibition of proliferation?

Answer 29

By acquiring mutation activation or epigenetic silencing.

Question 30

How do cancer cells gain immortality?

Answer 30

They express telomerase - replaces lost telomere sequences at each replication. Prevents the karyotypic chaos and apoptosis that results from fusion from the exposed ends of chromosomes,

Question 31

What is the function of p53?

Answer 31

Codes for TxF that induces Txn of >100 genes. Induces cell cycle arrest to allow repair of DNA damage but also induces apoptosis if there is too much damage.

Question 32

What results from in inactivation of p53?

Answer 32

Loss of apoptotic response - most common genetic abnormality in human tumours.

Question 33

What are the possible triggers of the p53 apoptotic response?

Answer 33

``` DNA damage Hypoxia Demethylation of DNA Viral infection Depletion of ribonucleotides Blockage of RNA/DNA synthesis ```

Question 34

How big can a tumour become without requiring angiogenesis?

Answer 34

2mm

Question 35

What is the mechanism for angiogenesis?

Answer 35

- Hypoxia stabilizes HIF-1 transcription factor, which induces vascular endothelial growth factor (VEGF) – an angiogenic factor - This actively recruit endothelial cells that proceed to construct new capillaries and vessels

Question 36

What is the function of E-cadherin?

Answer 36

Adhesion molecule that holds epithelial cells together.

Question 37

What happens if e-cadherin is lost?

Answer 37

- Results in epithelial-mesenchymal transition (EMT) - Mesenchymal cells are motile and secrete proteases - allows them to break through basement membrane and invade the underlying stroma - Metastasis involves the spread of malignant cells via the blood/lymphatic system to secondary sites and the formation of secondary tumours

Question 38

How might a specific tumour marker be used for better treatment?

Answer 38

- HER2 (+ve growth factor receptor) over-expression found in ~30% of breast tumours - Makes cells more responsive too, or independent of, +ve growth factors - Only patients with HER2 will benefit from Herceptin - monoclonal Ab to HER2