genetic basis of neoplasia

Question 1

what are the 6 hallmarks of cancer

Answer 1

1. sustaining proliferative signaling
2. evading growth suppressors
3. resisting cell death
4. enabling replicative immorality
5. inducing or accessing vasculature
6. activating invasion and metastasis

Question 2

what are the extrinsic environmental exposure causes of cancer

Answer 2

• gamma-irradiation
• UV light
• second-hand smoke
• chemicals

Question 3

what are the extrinsic infectious agents causes of cancer

Answer 3

• viruses (papillomaviruses & retroviruses)
• other infectious agents (H.pylori - gastric carcinoma, schistosoma - SCC of bladder)

Question 4

how do retroviruses cause cancer

Answer 4

• can activate oncogenes by insertional mutagenesis (activate oncogenes by inserting next to them and driving their expression from powerful viral promoters)
• can become acutely transforming oncoviruses (rare recombination event in which part of the viral genome is replaced by a cellular proto-oncogene, oncogen is now under control of the viral promoter)

Question 5

what are the intrinsic causes of cancer

Answer 5

• GENES
• cancer is an acquired genetic diease: cancer genes are altered in somatic cells
• contribute to cancer by boosting cell proliferation, blocking terminal differentiation, and suppressing apoptosis and accumulating DNA damage

Question 6

what are the key types of genes involved in intrinsic causes of cancer

Answer 6

• proto-oncogenes
• tumor-suppressor genes
• apoptosis genes
• DNA repair genes

Question 7

what are proto-oncogenes

Answer 7

• normal regulatory genes that promote cell growth
• can become oncogenes, leading to unregulated cell growth, when mutated or expressed at high levels
• oncogenes are always dominant - only need one mutated copy to get uncontrolled cell growth

Question 8

proto-oncogene

growth factor receptors (EGFR, c-Kit, Ras)

Answer 8

• engagement of receptors leads to receptor tyrosine kinase activity and initiates intracellular signal cascade through the G protein, Ras
• constitutive activity leads to uncontrolled cell growth

Question 9

proto-oncogene

transcription factors (Myc, NF-kB)

Answer 9

complex master transcription factors that regulate hundreds of genes involved in cellular proliferation

Question 10

proto-oncogene

cell cycle regulators (CDK, PIK3CA, cyclins)

Answer 10

control cell cycle progression - mutations leading to constitutive activity will promote cell cycle progression and accumulation of mutations since cell cycle will not stop to allow for DNA repair

Question 11

what is chromosomal translocations

Answer 11

place a proto-oncogen under the control of a constitutively active promoter

Question 12

what are tumor-suppressor genes (TSG)

Answer 12

• normal genes that suppress cancer growth
• mutation in TSGs are recessive - both alleles need to be inactivated to predispose to cancer
• ex: p53, retinoblastoma, NF-1

Question 13

tumor-suppressor genes

p53

Answer 13

transcription factor that regulated expression of genes that block cell cycle or induce apoptotic death

• activated in reponse to cell damage or adverse environment, preventing cellular proliferation and/or eliminating cells that are irreparably damage
• mutations lead to a failure to halt cell cycle; cells proliferate and accumulate mutations promoting oncogenesis

Question 14

mutations in p53 frequently result in its inability to bind to target genes:

Answer 14

• p21 (CDK inhibitor)
• Bax (apoptosis gene)
• GADD45 (DNA repair)