Tumor Suppressors

Question 1

What is a tumor suppressor?

Answer 1

A gene whose product acts to inhibit cancer and is inactivated in cancer by mutation/deletion or epigenetic signaling

Question 2

How would you recognize Retinoblastoma?

Answer 2

1) Leukocoria: Cat’s eye reflex - white reflex characteristic of retinoblastoma detected in photos
2) Proptosis: Protrusion of the eyeball with white reflex in right eye

Question 3

What is Knudsen’s two hit hypothesis?

Answer 3

Was studying retinoblastoma in children. Hypothesized that cancer developed when a child acquired two defective alleles. The first defective allele is inherited (first hit, germline) and the second defective allele is acquired later by a mutation in cell division of the child (second hit, somatic). Can be applied to other cancers also.

Question 4

Retinoblastoma

• Only 5% of carries (do/do not) display disease
• What is the inheritance pattern?

Answer 4

• Do not
• Autosomal dominant but a recessive mutation at the cellular level (inactivation of second allele allows dominant inheritance pattern of recessive mutation)

Question 5

Loss of heterozygosity is characteristic of ________

Answer 5

Tumor Suppressors

Question 6

What are the mechanisms that can lead to loss of heterozygosity?

Answer 6

Question 7

Why is p53 a tumor suppressor and not an oncogene?

Answer 7

Because individuals with mutations at the p53 locus display loss of heterogeneity which is characteristic of tumor suppressors

Question 8

Defects in Mismatch Repair

• When is mismatch repair used?
• How is the cleavage site determined?
• In normal function, how does this get repaired?
• What is the disease that occurs when these mismatch repair mechanisms are defective and how does that relate to tumor suppression?

Answer 8

• During replication, when and incorrect base pair has been created
• Methylations on the parental strand mark the cleavage site
• Exonuclease removes the mismatch by nicking DNA on either side of mismatch and removing DNA, DNAPol delta replaces removed DNA
• Lynch syndrome - if you cannot repair mismatches then those mutations will persist and be passed on to daughter cells and the individual is more likely to acquire mutations that result in cancer and mutations that result in loss of function of tumor suppressors

Question 9

Defects in Nucleotide Excision Repair

• What disease is associated with defects in nucleotide excision repair?
• How does this disease relate to tumor suppressors?

Answer 9

• Xeroderma Pigmentosum
• Nucleotide excision repair involves the removal of pyrimidine dimers or chemical adducts. If the body cannot adequately perform this function, then they are more likely to acquire mutations that result in carcinogenesis. This could be mutations that result in loss of function of tumor suppressors.

Question 10

Defects in Non-Homologous End Joining

What is ataxia?

What is telangiectasia?

How is ATM kinase related to NEHJ?

How do defects in NEHJ relate to tumor suppression?

Answer 10

• Ataxia - lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements
• Telangiectasia - (tiny blood vessels) cause threadlike red lines or patterns on the skin
• ATM is involved in loading Ku protein onto ends of double stranded breaks so that repair can occur
• Inability to repair double stranded breaks can lead to carcinogenesis and increased likelihood of loss of function mutation of tumor suppressors