14 - Molecular basis of Cancer

Question 1

How is a tumour formed

Answer 1

By the clonal expansion of a single precursor cell that has incurred genetic damage

Question 2

4 classes of genes that are the main ‘targets’ for ongogenic mutations

Answer 2

• Proto-oncogenes
• Tumour suppressor genes
• Apoptosis regulating genes
• DNA repair genes

Question 3

Proto-oncogenes

Answer 3

normal cellular genes whose products promote cell proliferation (growth factors, signal transducers, transcription factors)

Question 4

Tumour supressor genes

Answer 4

mutations are usually “loss of function”, so both copies need to be affected

Question 5

DNA repair genes

Answer 5

• Impair the ability of the cell to repair DNA damage
• Thus more mutations are acquired: “mutator phenotype”

Question 6

Driver mutations

Answer 6

Mutations that contribute to the development of the malignant phenotype

Question 7

What does cancer formation result from

Answer 7

The accumulation of mutations in a stepwise fashion over time

Question 8

Passenger mutations

Answer 8

Mutations that may have no phenotypic consequence (loss of function mutations are common early step)

Question 9

How do tumours evolve

Answer 9

• Under Darwinian selection
• Emergence of subclones within the tumour
• Leads to therapy resistance

Question 10

Epigenetic modifications

Answer 10

Inheritable modifications of DNA which is not related to a coding change (e.g. DNA methylation, histone modification)

Question 11

Oncogenes

Answer 11

mutated or over-expressed versions of proto-oncogenes that function autonomously, having lost dependence on normal growth promoting signals

Question 12

Oncoprotein

Answer 12

a protein encoded by an oncogene that drives increased cell proliferation through several mechanisms

Question 13

Mechanisms of Oncoproteins

Answer 13

• Constitutive expression of growth factors and their
  receptors, setting up an autocrine cell signalling loop
• Activation of signal transduction molecules
• Activation of transcription factors
• Increase the activity of CDK4)

Question 14

ERBB1

Answer 14

• Encodes the epidermal growth factor receptor (EGFR)
• Point mutations result in constitutive activation of the tyrosine kinase

Question 15

ERBB2

Answer 15

• Encodes receptor tyrosine kinase HER2
• Amplified in some breast cancers, leading to overexpression of the HER2 receptor

Question 16

ALK

Answer 16

• Receptor tyrosine kinase on chromosome 5
• In some lung cancers a fusion of EML4-ALK results in a chimeric EML4-ALK protein with constitutive kinase activity

Question 17

effects of a mutated MYC gene

Answer 17

• Activates the expression of genes involved in cell growth
• Upregulates telomerase expression
• Reprograms somatic cells into a stem cell-like phenotype

Question 18

Tumour suppressor genes

Answer 18

• Act as a ‘brake’
• Abnormalities of these genes lead to failure of growth inhibition
• Form a network of checkpoints which prevent
  uncontrolled growth

Question 19

How do tumour suppressor genes prevent uncontrolled growth

Answer 19

• Shut down proliferation
• Initiate apoptosis
• Promote differentiation

Question 20

Retinoblastoma (RB) Gene

Answer 20

• Directly or indirectly inactivated in most human cancers
• A key negative regulator of the G1/S cell cycle transition

Question 21

Hypophosphorylated RB gene

Answer 21

• RB exerts antiproliferative effects by binding and inhibiting E2F transcription factors
• Growth factor signalling leads to RB hyperphosphorylation and activation

Question 22

In cancer, how can RB function be compromised

Answer 22

• Loss of function mutations in RB
• Loss of function of CDK inhibitors
• Gain of function of CDK4 and cyclin D
• Viral oncoproteins that bind and inhibit RB

Question 23

Retinoblastoma tumour

Answer 23

• An intraocular malignancy of children
• Can be familial (autosomal dominant, bilateral) or sporadic (unilateral)

Question 24

TP53

Answer 24

• Tumour suppressor gene
• Mutations are acquired in both alleles in somatic cells
• Inheritance leads to a predisposition of “Li-Fraumeni syndrome”

Question 25

p53 in non stressed cells

Answer 25

p53 is degraded via an association with MDM2

Question 26

p53 in stressed cells

Answer 26

p53 is released from this inhibition and accumulates

Question 27

CDKN2A

Answer 27

Loss of function impacts both RB and p53 tumour suppressing pathways

Question 28

p16/INK4a

Answer 28

Blocks CDK4/cyclin D mediated phosphorylation of RB, reinforcing the RB checkpoint

Question 29

p14/ARF

Answer 29

Activates p53 by inhibiting MDM2 and stabilising p53

Question 30

Apoptosis

Answer 30

- Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program in which cells activate caspases that degrade the DNA and proteins - Protective response to conditions which may result in cancer

Question 31

Are mutations in DNA repair genes oncogenic

Answer 31

No, but enhance the occurrence of other mutations which might be

Question 32

DNA mismatch repair

Answer 32

- Correct single base errors (GT pairing rather than AT) - Inheritance of one mutant copy results in Familial carcinomas of the colon - These tumours are characterised by microsatellite instability

Question 33

Microsatellites

Answer 33

- Tandem repeats of 1-6 nucleotides found throughout the genome - Length remains constant - With loss of mismatch repair these satellites increase or decrease in length (unstable)

Question 34

Nucleotide Excision Repair

Answer 34

- UV radiation causes cross-linking of pyrimidine residues, preventing normal DNA replication (pyrimidine dimers) - Repaired by NER - Inherited loss of one of the genes involved in this system leads to increased risk of developing skin cancers

Question 35

Homologous recombination

Answer 35

- Defects in the homologous recombination cause group of disorders characterised by hypersensitivity to DNA damaging agents - Mutations in BRCA1 or 2 account for 25% of familial breast cancer - Cells with these mutations develop chromosomal breaks and abnormal numbers of chromosome

Question 36

Hereditary Leiomyomatosis and Renal Cell Cancer

Answer 36

- develop multiple smooth muscle tumours (leiomyomas) in the skin and uterus, as well as aggressive renal cell carcinomas - Caused by mutation in Fumarate hydratase

Question 37

Fumarate hydratase

Answer 37

- Enzyme acting within the Krebs cycle - catalyses the hydration of fumarate to malate - Mutations in Krebs cycle components lead to a decrease in oxidative phosphorylation

Question 38

Warburg effect

Answer 38

- Cancer cells tend to ferment glucose into lactate even in the presence of sufficient oxygen - “aerobic glycolysis”

Question 39

Possible explanations for the Warburg effect

Answer 39

- ATP is only an issue when resources are scarce - Proliferating cells have other metabolic needs besides ATP (Carbon atoms, Acetyl-CoA, NADPH)

Question 40

Angiogenesis

Answer 40

- Even if a tumour has all of the genetic mutations required for limitless growth, it cannot enlarge to more than 1 or 2mm due to a lack of blood supply - Promoting the growth of new blood vessels is critical to the survival of neoplasms

Question 41

Two phases of invasion and metastasis

Answer 41

- Invasion of the extracellular matrix - Vascular dissemination

Question 42

Can circulating tumour cells can be identified in patients without clinically overt metastatic disease?

Answer 42

Yes

Question 43

Immune response to tumour cells

Answer 43

- Tumour antigens are presented on the cell surface by MHC class I molecules and are recognised by cytotoxic T-lymphocytes. - Immunosuppressed patients have an increased risk for development of cancer, particularly types caused by oncogenic DNA viruses.

Question 44

Mechanisms of evasion of immune defences

Answer 44

- Selective outgrowth of antigen-negative variants - Loss or reduced expression of histocompatibility antigens - Expression of certain inhibitory factors by the tumour cells, which act to dampen the immune response