genetics of cancer

Question 1

6 hallmarks of cancer

Answer 1

sustaining proliferative signalling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, resisting cell death

Question 2

2 emerging hallmarks of cancer

Answer 2

deregulate cellular energetics, avoid immune destruction

Question 3

2 enabling characteristics of cancer

Answer 3

genome instability and mutation, tumour-promoting inflammation

Question 4

cell cycle: cycle checkpoints

Answer 4

G1/S (assess DNA damage), G2/M (assess duplicated DNA damage)

Question 5

cell cycle: what can permanent activation of a cyclin lead to

Answer 5

driving a cell through a checkpoint

Question 6

what do proto-oncogenes code for

Answer 6

essential proteins involved in maintenance of cell growth, division and differentiation

Question 7

effect of mutation (e.g. single point mutation) on proto-oncogene

Answer 7

converts it into an oncogene, whose protein product no longer responds to control influences

Question 8

3 ways oncogenes have expression or activity

Answer 8

aberrant expression, over-expression, aberrant activity

Question 9

examples of how oncogenes can gain aberrant activity

Answer 9

if mutation in coding sequence in proto-oncogene, can change binding domain of inhibitory protein so can’t bind, or affect phosphorylation sequence so becomes constitutively active and can’t be switched off, creating an aberrantly active protein

Question 10

example of how oncogenes can be over-expressed

Answer 10

if mutation in coding sequence in proto-oncogene which then undergoes gene amplification

Question 11

how can oncogenes have aberrant expression

Answer 11

chromosomal translocation where promoter put in front of gene which isn’t usually expressed (chimaeric genes), or insertional mutagenesis (e.g. viral infection)

Question 12

2 examples of aberrant expression is gained in oncogenes

Answer 12

strong enhancer increases normal protein levels to point where they can’t be shut off; fusion to actively transcribed gene overproduces protein, or fusion protein is hyperactive (e.g. Philadelphia chromosome)

Question 13

describe how Philadelphia chromosome doesn’t allow apoptosis

Answer 13

BCR (anti-apoptotic product) on chromosome 22 translocated in front of ABL (strong promoter) on chromosome 9, meaning cell doesn’t die as lots of anti-apoptotic signal

Question 14

2 types of cell receptors in cell which are involved in signal transduction (proto-oncogenes)

Answer 14

tyrosine kinase receptor, G-protein coupled receptor (triggers IC kinase cascade)

Question 15

examples of tyrosine kinase receptor phosphorylation cascade proto-oncogenes

Answer 15

met, neu, src, ret

Question 16

examples of G-protein coupled receptor phosphorylation cascade proto-oncogenes

Answer 16

ras, gip-2, raf, Pim-1

Question 17

examples of transcription level modulator proto-oncogenes

Answer 17

myc, fos, jun

Question 18

normal RAS activity to activate and inactivate RAF

Answer 18

to activate RAF, RAS is phosphorylated by GTP to form RAF/GTP dimer which activates downstream pathway; dephosphorylation of GTP to GDP switches RAS off

Question 19

down-regulated RAS activity by cancer mutation

Answer 19

can’t bind GTP, so consitutively targeted by GDP, so downstream path not activated

Question 20

mutant RAS aberrant activity by cancer mutation

Answer 20

fails to dephosphorylate GTP, so RAF constantly activated, so downstream path always activated

Question 21

RAS signalling pathway

Answer 21

ligand binds to receptor -> tyrosine kinase phosphorylation -> effectors phosphorylated/dephosphorylated -> activation of MAPK -> activation of ERK -> transcriptional regulation effect in nucleus

Question 22

tyrosine kinase proto-oncogene target

Answer 22

SRC (overexpression/C-terminal deletion)

Question 23

2 transcription factor proto-oncogene targets

Answer 23

MYC (translocation) and JUN (overexpression/deletion)

Question 24

2 G-protein proto-oncogene targets

Answer 24

Ha-RAS and Ki-RAS (point mutations)