Cancer as a genetic disease

Question 1

Explain the difference between somatic and germline mutations, and between driver and passenger mutations; summarise the evidence about the number of mutations of different types found in cancer cells

Answer 1

Somatic; occur in body cells, cannot be passed to offspring (90% cancers)

Germline; mutations in gametes, can be passed onto offspring

Passengers; mutations that don’t contribute to the development of cancer but have occurred during growth of cancer

Drivers; contribute to cancer development

Inherited cancer disorders:

Familial adenomatous polyposis

• Thousands intestinal polyps, one or more of which is likely to become cancerous
• Autosomal dominant
• >1% of all colorectal cancers
• Mutation of APC (adenomatous polyposis coli) gene which controls cell division
• Virtually 100% lifetime risk of cancer

HNPCC (hereditary non polyposis colorectal cancer)

• 3% of all cases,
• Most common inherited form (90% of familial cases)
• Mutation of MLH1 or MSH2 (DNA repair genes)
• Lifetime risk of cancer 80%

Question 2

Explain what oncogenes and tumour suppressor genes are, and why they are important in cancer

Answer 2

Oncogenes

• Proto-oncogenes: promote growth + proliferation in cells
• Activated into overdrive => oncogenes
• Signalling cascades + mitogenic pathway activation
• Examples: growth factors, transcription factors, tyrosine kinases
• Result in a GAIN OF FUNCTION
• 99% of teh cancers are sporadic and 1% has an inherited component

Tumour suppressors

• Regulate cell division, DNA damage checkponits, apoptosis, DNA repair
• Mutations => lose function=> faulty cell division
• Result in a LOSS OF FUNCTION

Knudson’s two hit hypothesis

• Hit 1; reduces transcript/protein level but is insufficient to cause a phenotypic effect
  
  • It requires the innactivation of the second allele ( Hit 2) which will ultimetely cause loss of transcription and the rise of a malignant potential

Question 3

Outline the contribution of chromosome rearrangements to the formation of gene fusions and their contribution to oncogenesis; explain how chromosome translocations are used to quantify residual disease in leukaemia

Answer 3

Translocations:

• when 2 intragenic regions fuse new genes with potentially oncogenic properties can arise

Example: chronic myeloid leukaemia

1. Clonal myeloproliferative disorder => overproduction of mature granulocytes
2. Middle ages/elderly
3. 3 phases:
   
   1. chronic (benign)
   2. accelerated (omnious)
   3. blast crisis (acute leukaemic, invariably fatal)

Philadelphia chromosome >90% t(9,22)= BCR-ABL1 fusion protein (tyrosine kinase)

• Chemotherapeutic targets: Imatinib (blocks ATP binding site of BCR-ABL1)
• No Philadelphia chromosome = BAD