Oncogenes and TSGs

Question 1

What are 3 types of protooncogenes/oncogenes and TSGs?

Answer 1

HER2
KRAS
C-myc

BRCA1/2
TP53
RB1

Question 2

Which protooncogenes and TSGs affect cell cycle checpoints and where?

Answer 2

Ras, Myc = metaphase + G1 checkpoint

pRb = G0
p53 = S checkpoint

Question 3

What are the 2 main type of conversion from protooncogene to oncogene?

Answer 3

Mutation in the gene = different oncoprotein to normal protein in cell

Oncoprotein expressed at higher levels (same as the normal protein)

Question 4

What are 3 ways a proto-oncogene can be activated?

Answer 4

1) Point mutation: variant in proto-oncogene

2) Gene amplification: multiple copies of gene

3) Chromosomal Translocation: fusion protein, disruption of reg. elements

Question 5

Describe proto-oncogene mutations

Answer 5

Proto-oncogene mutations causing cancer often have a DOMINANT phenotype and are rarely inherited (SOMATIC MUTATIONS)

Question 6

What does HER2 gene code for? & what kind of activity does it have?
What is needed for HER2 activation and how can HER2 cause cancer?

Answer 6

HER2 codes for human epidermal growth factor receptor 2 + has intracellular tyrosine kinase activity

Growth factors bind EGFR or HER3 and alter receptor conformation–> activation

HER2 dimerisation downregulates p27 protein tumor suppressor -> cancer
HER2 is amplified in ~20% of invasive breast cancers! Poor prognosis :(

Question 7

what are 2 therapies are used to target HER2 associated cancers? & compare their mechanisms

Answer 7

• Trastuzumab & pertuzumab= targeted monoclonal Ab.
• Both downregulate/ block HER2 gene expression
• Trastuzumab blocks ligand independent HER2-HER3 dimerisation
• Pertuzumab binds to extracellular dimerisation domain of HER2 (stopping HER2 gene expression)

Question 8

Function of KRAS/RAS/ What do their gene products do?
How to active RAS?
Explain RAS switch? + how mutation of this leads to cancer

Answer 8

• Ras proteins = cellular signal transducers - control transcription +regulate cell growth
• Activated receptor tyrosine kinases activate Ras proteins
• Normally Ras is tightly controlled via switch on/off
  On= bound to GTP. Off= GTP break up to GDP
• Point mutation (codons 12 + 13) = permanent “on” = permanent growth/proliferation

Question 9

What is c-myc?
3 things it is involved in?
How is c-myc involved in cancer?
Preventive stratgeies?

Answer 9

MYC: family of genes encoding for transcription factors

Involved in: increasing proliferation, metabolic transformation and metastatic capacity

Translocation between chromosome 8 (c-Myc proto-oncogene) & 14 (Ig heavy chain gene) = c-myc gene overactivation -> Burkitt’s lymphoma

Myc protein inhibitors + Myc protein destabilizing drugs

Question 10

What are tumour suppressor genes? + 4 ways they work?

3 egs of TSG’s?

Answer 10

Inhibit replication and proliferation of damaged cells by:
1) Repair of DNA damage (e.g. MLH1, BRCA1/2)

2) Apoptosis (TP53)

3) Blocking proliferation

4) Oncogene antagonists

BRCA1/BRCA2, TP53, RB1

Question 11

Describe the Knudson’s two-hit hypothesis and loss of function mutations in TSGs

Answer 11

Loss of function mutations are RECESSIVE

• however, 1 normal allele is sufficient for cellular control
• Therefore a 2nd hit” of normal allele causes Heritable cancers to develop (due to loss of heterozygosity)

Question 12

Compare BRCA vs PARP

Answer 12

BRCA1 and 2 are involved in repairing double stranded DNA breaks
however PARP: proteins which fix single stranded breaks

Question 13

Function of p53 (note TP53=gene, p53=protein)
What is it regulated by?
What effect do some TP53 mutations have?
How many cancers contains TP53 mutations?

Answer 13

In DNA damage, p53 stops cell cycle or induces apoptosis!
TP53 is regulated by MDM2, which targets p53 for degradation in lysosomes. This stops excess p53 accumulation and activity.

Some TP53 mutations have dominant negative effect ie mutant p53 interferes w remaining normal p53 = adenoma

50% cancers contain missense mutations in TP53 hotspots
2 alterations=loss of function= cancer

Question 14

Function of RB1 gene? + How is it inactivated?
Compare sporadic vs familial retinoblastoma

Answer 14

MAPK signalling -> CDK4 & CDK6 activation which phosphorylates RB
phosphorylated RB no longer represses E2F1
Activation of E2F1 target genes allows progression through S-phase

Question 15

What is the prevalence, treatment and prognosis of RB1 cancer?

Answer 15

1 in 20,000 children + 80 cases/year
90% present before 5 years
Treatment: surgery & radiotherapy
98% of cases are cured