Introduction to oncogenes

Question 1

What is the difference between proto-oncogenes and oncogenes?

Answer 1

proto-oncogene = normal cellular gene which regulate cell growth and or division and differentiation
oncogene = mutated proto-oncogene

Question 2

What are the 2 types of oncogene activation?

Answer 2

1. mutation in the gene results in a different oncoprotein to the normal protein
2. oncoproteins are the same as the normal protein but expressed at higher levels

Question 3

What are the alterations that occur in oncogenes?

Answer 3

1. point mutation - variant in proto-oncogene or in promoter/regulatory element
2. Gene amplification - c-myc
3. chromosomal translocation - creation of a fusion protein (BCR-ABL in CML) or disruption of regulatory elements

Question 4

What is required to promote tumrouigensis

Answer 4

single copy of oncogene - oncogene cause cancer with a dominant phenotype. Proto-oncogene mutations are rarely inherited - somatic mutations

Question 5

Describe HER2

Answer 5

encodes for part of the human epidermal growth factor receptor 2

• receptor dimerisation (with EGFR, HER3, HER4) is required for HER2 function
• in absence of ligand - receptors resume closed confirmation
• ligand = open confirmation
• HER2 only becomes activated by homodimerisation or heterodimerisation with HER2

Question 6

Describe activity of HER2

Answer 6

• HER2 protein has intracellular tyrosine kinase activity

- HER2 is amplified in 20% of the invasive breast cancers and is associated with aggressive disease and poor prognosis

Question 7

What targets HER2?

Answer 7

• Trastuzumab and pertuzumab are monoclonal antibodies that target HER2 - targeted therapy
• only effective in HER2+ cancers

Question 8

What is KRAS?

Answer 8

• Ras proteins are cellular signal transducers
• KRAS - GDP = inactive
• KRAS - GTP = active

Question 9

Where are the point mutations in KRAS?

Answer 9

• codons 12 and 13 and 18, 61, 117 and 146

Question 10

Which cancers are affected by KRAS?

Answer 10

• Pancreatic - 90%
• Colon - 30-50%
• small intestine - 35%

Question 11

Describe the BCR-ABL1 oncogene

Answer 11

• 95% of chronic myeloid leukaemia (CML) have a detectable philadelphia chromosome
• result of balanced chromosomal translocation between chromosome 9 and 22
• BCR - chr 22
• ABL - chr 9
• fuse together = philadelphia chromosome

Question 12

What are the roles of BCR and ABL

Answer 12

• BCR - encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins
• ABL - encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition) - only transcribes necessary
• BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity

Question 13

What happens when unregulated BCR-ABL is produced

Answer 13

• proliferation of progenitor cells in the absence of growth factor
• decreased apoptosis
• decreased adhesion to bone marrow stroma

Question 14

Therapy for BCR-ABL mutation

Answer 14

• drugs that specifically inhibit BCR-ABL1 eg. imatinib - cases negative for BCR-ABL1 require different therapy
• imatinib prevents phosphorylation of substrates by BCR-ABL onco-protein (inactive

Question 15

Describe c-myc

Answer 15

• myc - family of genes which code for transcription factors

- induce cell proliferation, growth, loss of differentiation and apoptosis

Question 16

What occurs as a result of myc activation

Answer 16

molecular changes - inc. transcription, inc. mitochondrial biogenesis and function, inc. glycolysis
cellular changes - inc. cellular proliferation, inc, metabolic transformation

Question 17

What alterations occur in c-myc

Answer 17

• insertion of a retrovirus - between exons 1 and 2 of c-myc in the same transcriptional orientation is commonly found in bursal lymphomas in chicken
• virual genome is reverse transcribed into DNA
• viral DNA enters nucleus and inserts into host genome to become pro-virus
• once inserted exon 1 is no longer detectable, new gene (oncogene c-myc) is regulated by viral promoter

Question 18

Describe translocation in c-myc

Answer 18

• translocation between chromsomes 8 (c-myc proto-oncogene) and chromosome 14 (immunoglobulin heavy chair gene) are commonly found in Burkitts lymphoma

Question 19

Describe therapies targeting c-myc

Answer 19

• lack of strategies to directly target myc

- inhibitors of its translocation and Myc protein destabilising drugs show more promise