5 The molecular basis of cancer

Question 1

Mutations of what genes cause cancer?

[which one causes gain of function mutations]

Answer 1

(Proto)-Oncogenes

• They promote cell proliferation (most regulate proliferation)
• Gain of function mutations in cancer

Question 2

Mutations of what genes cause cancer

[which ones cause loss of function mutations]

Answer 2

Tumour suppressor (TS) genes

• They inhibit events leading to cancer (most regulate proliferation, immortality + apoptosis)
• Loss of function mutations in cancer

Question 3

List the main types of mutations

Answer 3

There are a wide range of mutations that can either block or augment gene function
- Gain of function
- Loss of function
=

Question 4

Describe the effects of a gain of function mutation

Answer 4

• Over-expression: amplification/changes to regulatory regions
• Point mutations
• Fusions

Question 5

Describe the effects of a loss of function mutation

Answer 5

• Point mutations
• Deletions - with frameshift
• Loss of allele

Question 6

Describe how to identify key cancer genes?

Answer 6

• Cellular and biochemical studies of normal cells and tumours
• Find genes commonly damaged in cancers
• Best approached is now whole-genome analyses

Question 7

Describe the study of familial cancers

Answer 7

Familial syndromes:
- Retinoblastoma
- Colon cancer
- Breast cancer
Familial cancers are rare. However, studying these syndromes has helped to identify some important cancer genes (especially TS genes)

Question 8

What is the two-hit hypothesis (for retinoblastoma)

Answer 8

Knudson (1970s) proposed ‘2-hit hypothesis’ based on tumour-formation timescales:

• Familial: caused by single random somatic event
• Sporadic: require two random somatic event

The theory was later conformed, and RB gene identified through genetic-linkage studies

Question 9

Explain how familial retinoblastoma shows autosomal dominant inheritance

Answer 9

• Retinoblastoma phenotype is dominant at the level of the whole organism
• However, the phenotype of the mutant allele is recessive at the cellular level (i.e. Rb/Rb cells are not cancerous)

Question 10

Explain why TS genes are associated with loss of heterozygosity in tumours

Answer 10

• Highly unlikely for sporadic mutation to inactivate both copies by two successive mutational events
• The second mutation occurs by a different mutational process with a higher frequency
  > one possibility is mitotic recombination
  > associated with loss of heterozygosity (LOH) for region containing the RB gene

Question 11

Describe the relationship between tumour suppressors and apoptosis

Answer 11

• When things go wrong, cells can commit suicide
  > known as ‘programmed cell death’ or apoptosis
• This is a mechanism to avoid cancer
• Proteins such as p53 can trigger cells to enter apoptosis if cell cycle/DNA synthesis fails to complete correctly

Question 12

How do tumour suppressors act?

Answer 12

TS proteins detect errors, mediate repair, inhibit replication or mediate entry to apoptosis
- loss of tumour suppressors means unprepared errors do not stop proliferation

Question 13

What are oncogenes?

Answer 13

Oncogenes are mutated (or occasionally viral) forms of genes involved in a range of processes:

• Secreted growth factors (e.g. PDGF-B)
• Cell surface receptors (e.g. EGFR)
• Signal transduction components (e.g. RAS)
• Transcription factors (e.g. myz)

Question 14

How are oncogenes formed?

Answer 14

There are a variety of ways that oncogenes are formed:

• Deletion or point mutation in coding sequence
• Regulatory mutation
• Gene amplification
• Chromosome rearrangement