L8 oncogenes

Question 1

what are the hallmarks of cancer?

Answer 1

• sustaining proliferative signalling
• evading growth supressors
• evading the immune system
• enabling replicative immortality
• promoting inflammation
• invasion and metastasis
• angiogenesis
• genome instability, mutations, dna repair
• resisting cell death
• altered cell metabolism

Question 2

what are the two egfr mutations and how do they cause oncogenesis?

Answer 2

l858r= single amino acid substitution= increases kinase activity by 50 fold= super charge egfr= more signalling

deletion of aa 747-752= stabilises dimer. in frame. super charge activity

Question 3

why are there ras and egfr mutation hotspots?

Answer 3

hotspot regions encode important functional domains
most oncogenic mutations are missense

Question 4

examples of oncogene amplification in cancer

Answer 4

mycn = neuroblastoma

c-myc = small cell lung cancer, breast, ovarian

egfr = glioblastoma

Question 5

what does FISH stand for and how does it work?

Answer 5

flourescence in situ hybridisation
chromosomes hybridised to flourscently coloured labelled probe- picks up mycn or chromosome 2. visualise additional copies.

Question 6

how can we test for n-myc prptein expression?

Answer 6

immunohistochemistry
nmyc positive= brown stain
lots= overexpression

Question 7

what are the three different chromosmal translocation in Burkitt Lymphoma?

Answer 7

t(18:14) - MYC-IgH
t(2:8) - MYC-IgK
t(8:22) - MYC-IgL

Question 8

c-myc is a transcription factor which drives transcription of what genes?

Answer 8

cell growth
proliferation
protein synthesis
metabolism

Question 9

what translocation occurs in follicular lymphoma? what chromosome are they found on? how does this lead to oncogenic activation?

Answer 9

BCL2-IGH translocation
BCL2= CHROMOSOME 18
igH= CHROMOSOME 14
bcl2= pro-survival gene, anti-apoptosis
thus resistance to chemo

Question 10

what is chronic myeloid leukaemia?

Answer 10

differentiation of myeloblast goes wrong
= too many granulocytes

Question 11

what is the translocation found in chronic myeloid leukaemia? what chromosome are these genes found on?

Answer 11

BCR-ABL
abl= chromosome 9
bcr= chromosome 22

Question 12

what drug can be used for chronic myeloid leukaemis with a BCR-ABL translocation?

Answer 12

imatinib
inhibitor of BCR-ABL tyrosine kinasse
competitive inhibitor of ATP binding site

Question 13

what drugs can be used for non-small cell lung cancer with EGFR mutations?

Answer 13

gefitinib= competitive ATP reversible binding. frequent resistance

afatinib- irreversible binding to ATP pocket

osimertinib- bind more avidly to EGFR T790M mutants vs wild-type

PRECISION MEDICINE:
ras- sotorasib
raf- venurafenib
mek- selmetinib