Genetics of malignancy 2

Question 1

Overcoming G1/S checkpoint

Answer 1

Upregulation of TFs (Myc oncogene) leads to increased cyclin D-cdk4 (G1-Cdk) activity

Question 2

Rb protein

Answer 2

Active Rb binds and inactivates E2F
Active G1-Cdk phosphorylates Rb (inactive) and releases E2F
Active E2F allows S-phase genes to be transcribed and DNA synthesis

Rb lost in cancer, allowing unregulated S-phase entry
Variety of inactivating mutations in RB1 gene

Question 3

Sporadic retinoblastoma

Answer 3

Somatic mutation leads to one mutant Rb allele. Second somatic mutation in other allele occurs
Leads to unilateral form (1 eye)
Cured by tumour removal

Question 4

Familial retinoblastoma

Answer 4

Cancer-predisposition syndrome
1 allele already mutated in fertilised egg. First somatic mutation leaves two mutant Rb alleles
Leads to bilateral form (both eyes)

Question 5

p53

Answer 5

Encoded by TP53 gene
Regulates genes involved in cell cycle arrest (p21)
DNA repair (XPA)
Angiogenesis inhibition (TSP-1)
Apoptosis

Question 6

p53 activation

Answer 6

In normal conditions, p53 is bound by Mdm2 (E3 ub ligase) and degraded by the proteasome
DNA damage activates ATM/ATR kinase. Chk1/2 kinase activate and phosphorylate p53
Mdm2 polyubiquitinates itself
p53 activated

Question 7

p21

Answer 7

p53 binds regulatory region of p21 gene and p21 transcribed

p21 binds and inactivates G1/S-Cdk, leading to cell cycle arrest

Question 8

Arf

Answer 8

Expression induced by excessive Myc production (oncogenic signalling)
Binds and inactivates Mdm2
Stable active p53 leads to cell cycle arrest or apoptosis
Loss of p53 leads to apoptosis evasion and unregulated cell growth

Question 9

Telomeres

Answer 9

Excess DNA that protects ends of chromosomes

Shorten with successive cell generations (regulation)

Question 10

Telomerase

Answer 10

Resynthesises telomeres
Normally only expressed in germ and stem cells
TERT gene overexpressed in cancer leading to replicative immortality

Question 11

Deregulation of cellular energetics

Answer 11

Normal cells divert most pyruvate to citric acid cycle
Cancer cells overexpress GLUT1 transporters and take up more glucose
Rely on aerobic glycolysis for energy, allowing more biosynthesis

Question 12

Original hallmarks of cancer

Answer 12

Sustaining proliferative signalling (growth-promoting oncogenes)
Evading growth suppressors (loss of TSGs)
Activating invasion/metastasis
Enabling replicative immortality (telomerase)
Inducing angiogenesis
Resisting cell death (loss of TSGs and gain of oncogenes)

Question 13

Thrombospondin-1

Answer 13

Extracellular matrix glycoprotein
Negative regulator of angiogenesis
Activates TGF-beta which negatively regulates haematopoiesis
Inactivation of p53 results in loss of TSP-1