oncogenes and tumour suppressors Flashcards
what are the hallmarks of cancer *
sustaining proliferative signalling
evading growth suppressors
activating invasion adn metastasis
enabling replicative immortality
inducing angiogenesis
resisting cell death
what are the emerging hallmarks and enabling characteristics of cancer
emerging hallmakrs - deregulating cellular energetics (can depend on anaerobic resp), avoiding immune destruction
enabling characteristics - genome instability and mutation, tumour promoting inflamm (can alter propagation and cancer therapy)
describe how the cycle fits in with cancer *
cycle checkpoints - growth arrests to ensure genetic fidelity
G1/S checkpoint - check DNA damage and if there is damage arrests the cell cycle and uses different repair genes eg RAD51 like proteins, BRCA1/2 - if cant repair cell goes into apoptosis
G2/M checkpoint - check for damaged DNA and check that all DNA has been adequately duplicated
specific proteins accumulate/are destroyed by the cycle - cyclins, cdks, cdk inhibitors
permanent activation of a cyclin can drive a cell through a checkpoint
what are proto-onchogenes *
they code of essential proteins involved in maintenace of cell growth, division and differentiation
how is a proto-oncogene related to an oncogene *
mutation converts a proto-oncogene to an oncogene - whose product no longer responds to control influences
eg upregulation of K-Ras seen in colorectal cancer - provides stimulus for unchecked, uncontrolled support of cancer clone
this can be through a single mutation
oncogenes can be aberrantly expressed, overexpressed or aberrantly active eg MYC RAS ERB SIS
- overexpression - HER2 in breast cancer, this is a cell cycle receptor that drives the mutation (look to see how much is present to know if a patient would benefit from herceptin)
overall there is a change in the activation protein menaing that it cant be switched off - perhaps so off signal cant bind, or it doesnt respond to the offsignal
describe oncogene activation *
normal proto-oncogene - driving, surveillance or stimulation, but controlled
- mutation in the coding sequence = change in the binding domain of inhibitory protein so gene cant be switched off anymore eg by affecting phosphorylation sequence aberrently active protein
- gene amplification - multiple gene copies all are expressed - overproduction of normal protein - eg HER2 in breast cancer and some gastrooesophageal cancers
- chromosomal translocation (chimaeric genes) or insertional mutagenesis (viral infection) - strong enhancer increases normal protein levels to a point you can’t shut off, of genes that are not normally expressed well eg Butkitt’s lymphoma; or get fusion to activelaly transcribed gene overproduces protein or fusion protein in hyperactive
describe the philidelphia chromosome *
present in some leukaemia
ABL is a strong promotor sequence
Bcr is an anti-apoptosis gene
when have ABL translocated on to bcr = strong anti-apoptosis signal
describe proteins involved in signal transduction *
tyrosine kinase receptor - ehn activated they send signals through kinases
G-proteins stimulation triggers intracellular kinases
what are proteins that are involved at different points in signal transduction in cancer *
EGFR mutations in lung cancer, met and neu at TK receptor - neu is acronym for HER1,2,3 receptor complexes
src, ret - pancreatic, breast and prostate cancer
myc, fos, jun at transcription level
G coupled protein receptors - ras, gip1,
ras raf pathway - raf and pim-1
what is the problem targeting genes higher up in the signal transduction pathway *
things upstream in the system have a lot of effects further down
eg if you try to target EGFR it will have a lot of effects in differnet cancer
effect of mutation in RAS *
mutant RAS fails to dephosphorylate GTP and so remains active
even when can dephosphorylate doesnt get switched off anyway
mutation present in non-small cell lung cancer and colorectal cancer
consequence of RAS signalling *
produces all of the things necessary to be alive - for proliferation adn survival
therefore if cell is heavily mutated with cancer - but oncogene is switched on so can still do this pathway - means cancer will be able to survive
SRC *
function - TK
mechanism in cancer - overexpression because of deletion at the c terminal
it is cytoplasmic
associated cancers - breast, colon, lung and haematological
MYC *
TF
mechanism in cancer - translocation
it is nuclear
imvolved in Burkitt’s lymphoma
JUN *
TF
overexpressed because of deletion
cytoplasmic
bladder cancer
Ha-RAS *
G protein
point mutation
cytoplasmic
bladder cancer
Ki-RAS *
G protein
point mutation
cytoplasmic
colon/lung
what is the significance of mutations *
different in different cancers
ie drugs that work in RAS mutation for colorectal cancer dont work for lung cancer with same mutation and vice versa - therefore more is important than just the driving mutation
describe tumour suppressor genes *
typically proteins whose function is to regulate cellular proliferation and maintain cell integrity
eg RB (checkpoint at G1/S to make sure DNA repair has been done)
each cell has 2 copies of a tumour suppressor gene
mutation of deletion of 1 is USUALLY insufficinet to promote cancer
mutation/loss of both copies means loss of control
however, need to be aware of haploinsufficiency - some genes/circumstances mean 1 mutation is enough to cause cancer phenotype
describe knudson’s 2 hit hypothesis *
hereditory cancer - some people have 1 inherited mutation of tumpur suppressor genes - then when acquire one = cancer phenotype
sporadic cancer - need need mutations in 2 copies of same gene
therefore sporadic are rarer than corresponding hereditory
be aware haploisufficiency - some cancers only need 1 hit
describe features of inherited cancer suseptibility *
FH of related cancers
unusually early age of onset
bilateral tumours in paired organs
synchonous or successive tumours
tumours in different organ systems in the same individual - worry about a p53 mutation
mutation inherited through the germline eg BRCA mutation - to be screened have to have strong FH, or triple -ve breast cancer
multiple primaries of the same tumour
describe retinoblastoma *
one of the 1st conditions where we realised inherited predisposition
it is malignant cancer of developing retianl cells
sporadic disease usually occurs in 1 eye, hereditory can by unilateral/bilateral
due to mutation of RB1 tumour suppressor gene on chromosome 13q14
RB1 encodes a nuclear protein that is involved in regulation of the cell cycle - involved in cdk 4 and 6 - move cell from G1 to S phase
what are the functional classes of tumour suppressor genes *
regulate cell prolif
maitain cellular integrity
regulate cell growth
regulate the cell cycle
nuclear TF
DNA repair proteins
cell adhesion molecules
cell death regulatiors - regulate apoptosis
(they all suppress the neoplastic phenotype)
p53 *
tumour suppressor gene
cell cycle regulator
nuclear
associated with many cancers eg colon, breast, bladder lung - because it is ubiquitous means it is difficult to target
BRCA1 *
tumour suppressor gene
cell cycle regulator by atm, atr or RAD3 like protein - involved in single strand break repair - if you outcompete single strand break repair, BRCA1 can push DNA down double strand repair pathway by non-homologous end joining or homologous recombination repair
nuclear
breast ovarian prostate
PTEN *
tumour suppressor gene
involved in cowden syndrome
tyrosine and lipid phosphtase
cytoplasmic
prostate and glioblastoma
APC *
tumour suppressor gene
function - cell signalling
cytoplasmic
colon cancer
p16-INK4A *
tumour suppressor gene
cell cycle regulator
nuclear
for colon and other cancers
new drugs developed for ER positive, HER2 -ve, metastatic breast cancer - called cdk4/6 inhibitors eg abemocyclib - have possibility to work in p16 pts so given in trials to small cell ling cancer, colon cancer, mesothelioma
MLH1 *
tumour suppressor gene
mismatch repair genes
nuclar
colon gastric
what does it mean that tumour suppressor genes are embryonically lethal *
if the mutations occured in embryo - the child wouldnt be born
describe the roles of p53 *
it is a tumour suppressor gene
things taht activate p53 - oxidative stress, NO, hypoxia, ribonucleotide depletion, mitotic apparatus dysfunction. oncogene activation, dna replication stress, double strand break, telomere erosion
p53 is involved in regulation of p53 target genes and protein-protein interactions
p53 target genes cause metabolic homeostsis, antioxident defence, dna repair, growth arrest, senescence, apoptosis - as go from mild and physiological stress to severe stress
p53 partners with MDM2 (mitotic regulator) - regulates itself eg when high oxidative stress - p53 will upregulate itself
describe p53 in cancer *
need to know if it is a driver or passenger mutation - as it is involved in a lot of systems can ofter be passenger mutation - therefore targetting it would not cure the cancer
targetting p53 is impossible - we cnat effect all the differnet pathways and also effect healthy tissues
if you have p53 mutation - poor prognosis - early and multimalignancies and get less common cancers eg sarcoma
although it is a tumour suppressor gene - mutants of p53 act in a dominant manner - so mutation of a single copy is sufficient to get dysregulation of activity
describe cancer from APC mutation *
APC is a tumour suppressor gene - is a driver in familial adenomatous polyposis coli (colorectal cancer)
due to a deletion in chromosome 5q21 resulting in loss of APC gene
apc gene is involved in cell adhesion in stroma of anchoring and not anchoring, and MAPK signalling
suffers get multiple benign adenomatous polyps in the colon
there is 90% risk of developing colorectal carcinoma
mechanism of APC *
participates in the WNT signalling pathway
it is a negative regulator of B-catenin
B-catenin has a role in division and adhesion
therefore APC prevents uncontrolled cell division
mutation of APC is frequent in colon cancer - allows dysregulation of cell division and cell architecture and anchoring role
summarise the route to cancer *
when have mutation in proto-oncogene - create environment for cancer, but the tumour suppressor gene buts a break on this
when have mutation in tumour suppressor but proto-onco is fine - not a cancer prone environment but removed the breaks
if have oncogene and mutation of tumour suppressor - leads to cell growth and proliferation = cancer
describe the development of colorectal cancer *
have normal epi
mutation in APC (tumour suppressor) = hyperproliferation of epithelium = proliferation is faster so have more risk of a point mutation
K-Ras (oncogene) mutation and DNA hypomethylation leads to adenoma
p53 mutation is a passenger mutation but causes carcinoma
carcinoma can metastasis
the path goes from hyperplasia to metaplasia to dysplasia to carcinogenesis
summarise oncogenes *
gene active in tumour
specific translocations/point mutations
mutations rarely hereditory
dominant at cell level
broad tissue specificity
found in leukaemia and lymphoma
summarise tumour suppressor genes *
gene inactive in tumour
deletions or mutations
mutations can be inherited
recessive at cell level
considerable tumpur specificity
solid tumours
describe COSMIC
catalogue of somatic mutations in cancer
give location and therefore meaning of a mutation - allow us to determine whether a tumour will respond to treatment
this is important for precision medicine
