Inherited Cancers

Question 1

What are the three different types of inherited cancer predisposition genes?

Answer 1

• Proto-oncogene: promote cell proliferation
• Tumour suppressor gene: inhibit cell proliferation
• Mutator gene: maintain integrity of the genome

Question 2

Provide some examples of mutations in tumour suppressor genes causing cancer syndromes

Answer 2

• TP53: Li-Fraumeni syndrome
• BRCA1/2: Breast and ovarian cancer
• PTEN: Breast and thyroid cancer, Cowden syndrome
• APC: Familial adenomatous polyposis (FAP)

Question 3

Provide some examples of mutations in genes maintaining the integrity of the genome causing cancer syndromes

Answer 3

• Mismatch repair genes: mainly MLH1 and MSH2 - result in colorectal, endometrial, ovarian and other tumours (=Lynch syndrome)
• DNA repair defects: mutations in caretaker genes that protect against DNA damage from radiation, free radicals and exogenous chemicals

Question 4

How is FAP diagnosed?

Answer 4

• Greater than 100 colorectal adenomatous polyps OR

- Fewer than 100 polyps but a first degree relative with FAP

Question 5

What is Knudson’s two hit hypothesis for a sporadic/hereditary tumour?

Answer 5

• Gene mutations may be inherited or acquired during a persons life
• A cell can initiate a tumour only when it contains 2 mutant alleles
• In the case of hereditary tumours, the first mutation is present in the all cells of the predisposed patient but the second mutation arises in somatic cells in the organ in which the tumour then develops

Question 6

Give three examples of DNA repair defect pathways

Answer 6

1. Nucleotide excision repair (linked to Xeroderma pigmentosa)
2. transcription-coupled repair (linked to cockayne syndrome)
3. Cross-linking agent repair (linked to Fanconi Anaemia)

Question 7

What happens if your helicase is defective?

Answer 7

Bloom syndrome: absence of BLM protein destabilises the enzymes important in DNA replication and repair

Question 8

What are the key features of familial cancer predisposition?

Answer 8

• Early onset tumours
• Multiple tumours in close relatives
• Multiple tumours within an individual
• Clusters of different tumours in recognisable pattern

Question 9

What are the options available for modification of risk?

Answer 9

• Surveillance
• Prophylactic surgery and/or chemoprevention
• Diagnostic/predictive molecular genetic testing