Lecture 8 - Tumour Supressor Genes NOT FINISHED

Question 1

What are the two places where mutation in TSGs can occur

Answer 1

Inherited syndromes = mutations present in every cell (germ line)
Sporadic/Somatic cancers = mutation only in cell where cancer originates

Question 2

What are the characteristics of tumour suppressor genes?

Answer 2

• The protein products of TSGs function to negatively regulate cell growth, and/or are components of cell cycle checkpoints that ensure genomic integrity in response to genotoxic stress
• Loss of TSG function means loss of growth suppressive function and/or loss of cell cycle checkpoint control. Results in enhanced proliferative pontential
• they are recessive in cancer, Both alleles of TSG must be eliminated or inactivated to abolish Tumour
• two hit hypothesis
• Inherited - one mutation in germ line, second mutation somatic
• Non-hereditary - both mutations are somatic

Question 3

Describe the differences between somatic and familial retinoblastoma

• mutation timing
• bilateral/unilateral disease
• onset
• susceptibility to non-retinal tumours

Answer 3

Familial 
- mutant RB alley 
- first somatic mutation 
- two mutant RB gene copes 
- bilateral disease 
- early onset
- high susceptibility to non-retinal tumours 
Somatic 
- first somatic mutation 
- mutant RB allele
- second somatic mutation
- two mutant RB gene copies 
- unilateral disease
- late onset 
- low susceptibility to non-retinal tumours

Question 4

Describe the tumour in retinoblastoma and its effects

How do children present?

Answer 4

Cancer of the retina
Displaced normal retina
Thickening of optic nerve due to extension of tumour
- White light reflection 
- Squint

Question 5

What is the treatment for childhood retinoblastoma?

Answer 5

lasertherapy
cryotherapy
thermotherapy
chemotherapy
surgery
radiotherapy 
90% cured (UK)

Question 6

How is RB inactivated in retinoblastoma?

Answer 6

• large deletions
• single base substitutions
• small length mutations
• most mutations are associated with almost complete penetrance
• rare alleles show incomplete penetrance and reduce expressivity
• loss of heterozygosity
• hypermethylation of the 5’ region of the RB1 gene
• mitotic recombination, mitotic nondisjunction, large deletions

Question 7

How is RB inactivated in somatic retinoblastoma?

Answer 7

gene deletions, base substitutions, small length mutations

Question 8

What is loss of heterozygosity at the retinoblastoma locus?

Answer 8

• One mutant Rb allele (heterozygosity)
• S phase chromosome replication, 2 mutant alleles on one chromosome, 2 normal on the other
• G2 and M phases of cell cycle –> mitotic recombination
• segregation of chromatids at end of mitosis
  1. Retention of Rb heterozygosity
  or
  2. loss of Rb heterozygosity in daughter cells