cancer Flashcards
what are the typical patterns of mutations for a proto-oncogene compared to a TumorSupressor gene? (how can we distinguish a
there would be missense mutations in clustered areas which would indicate a GOF mutation
there would be very few/none non-sense (trunchate) mutations as that would mean the function of the gene is lost
i would say a non-sense mutation more common for a tumour supressor gene which can happen all over the gene, not a hotspot
how does cancer relate to aging?
as we age, more likely we are exposed to more carcinogens and also more likely that we will accumulate mutations
there is also global demethylation but increased methylation at CPG islands so more likely for a caretaker gene or a TS to be switched off
which type of cancer is makes up 1.5% of all cancers? A sarcoma B carcinoma C lymphoma/leukamia D neuroectodermal
OPTION D - neuroectodermal
80% carcinoma
1% sarcoma
7% leukiamea
what is dysplasia?
tissue that is in a pre-malignant state
> hyperchromatic nuclei
> lacks differentiation markers
> looks abnormal
describe how myeloid leukaemia can develops
what actually causes the onset of ML?
chronic ML - this is the benign stage and cells appear to be abnormal and have multi-lobed nuclei
acute ML - this is the malignant / this is cancerous as the cells have hyperchromatic nuclei, lack differentiation markers and can metastasize
CAUSED BY PHILIDELPHIA CHROMOSOME/ BCR-ABL - TYROSINE KINASE
what are driver and passenger mutarions
driver - mutations that result in growth or survival advantage in cancer cells
> average 4.6 driver needed to cause cancer
passenger - coincidental mutation with no advantage to cancer phenotype
Sanger institute - different number of driver mutations drive cancer of different organ
> 11 GIT, 2kidney, 6brain+lung, 4liver+breast
karyotype and cancer
cancer cells have abnormal karyotypes which promote genomic instability
> aneuploidy +- or polyploidy (duplicaton)
> translocations
> deletions
> chromothrispis
what is chromospthrispis? what is consequence of chromothripsis in cancer?
single event where chromosome is fragmented and then put these fragments are reaaranged and fused together via NHEJ
> not all fragments are incorporated = deletion
> lead to circularisation and creation of double minute chromosome which can aplift
can mean a cancer cell aqquires multiple driver mutations at once greatly speeding up disease progression
where do cancer cells derive from
from a single progenitor cell so they all share gentic info / genetic homeogeinity
> so they are monoclonal
usually a mutation of stem cells which gives it a greater ability to metastatise
why do cancer cells show heterogeneity within a tumour mass if they are genetically identical?
cancer stem cells seem to be the tumour subpopulation of cells which can maintain the cancer and responsible for migratory ability of cancer
> these cells most likely to resist cancer therapy
what are key differences between normal and cancer cell
~~~
cancer cells can
> be migratory (via EMT) lack polarity
> lack differentiation markers
> hyperchromatic and multi nucleic
> look abnormal
what results in formation of proto-oncogene
- qualitative: formation of abnormal protein due to SNP or translocation = fusion protein/ strong promoter (22:9), or even virus oncoproteins
- Quantitative: OE of protein (GF, GFR) due to could be due to chromosome translocation to a strong promoter (8:2,14,22 burkitts lymphoma MYC), SNP, gene duplications/amplifications
how can a LOF of a TS gene occur ?
LOF TS gene is recessive so there is an element of heritability
> deletions, SNP or frameshift = truncation, epigenetic silencing as we age
hpv oncoprotein E7 degrades Rb
what is a TS gene? can you name some examples?
a gene that promotes apoptosis and inhibits cell proliferation
a caretaker gene is involved in DNA damage repair
> p53, PTEN, p16, p17, p21 - cdk inhibitor, Rb
how can we detect these driver mutations
use large scale genomic sequencning
what do proto-oncogenes do? how does it achieve its function?
promotes cell proliferation and inhibits apoptosis
signals via the MAPK pathway using growth factors
> so mutation in any of these signal transduction cascade elements can drive tumorgeneis/sustain proliferation
what is cancer?
refers to a malignant neoplasm/tumour
this can metastasize and invade cells, appears abnormal
cancers can be classified according to their (tissue) origins. Name the 4 subtypes
carcinomas (80% all cancers) origin epithelial cell
sarcomas orgin from the mesenchymal cells (CT, mesoderm, neurons, bone muscle), rare only 1%.
leukaemia and lymphomas origin haemotopoietic cells 7% tumours.
glio/neuroblastomas origin from neuroendodermal tissue 1.5%
> not all fit into these 4 catergories e.g melanomas, lung carcinoma
give an example of how a benign tumour can evolve into a cancer
barrets oesophagus characterised by metaplastic tissue where there is abnormal replacement of squamous cells to collumnar epithelium
more likely to develop into malignant oesophageal adenocarcinoma
> also a common mole can develop into a melanoma
name some of the ESTABLISHED hallmarks of cancer
excessive cell proliferation
can evade the growth inhibitory signals
can evade apopotosis/cell death
are replicatively immortal
induce angiogeneisis
can undergo metastasis and invasion
name the cellular changes that distinguish cancer cell from a normal cell
enhanced stimulation of growth factors
hyperplastic , metaplastic
Poorly differentiated
Looks abnormal
multilobed nuclei
what is the difference between a benign and malignant neoplasm?
benign are non-invasive and localised. they exhibit hyperplastic and metaplastic characteristics
malignant are invasive, can undergo metastasis and spread to other locations and form secondary tumours
define hyperplastic and metaplastic
hyperplastic - excessive cell number as cell proliferation is dysregulated
metaplastic - ectopic cell replacement and usually seen in epithelial transition zones (e.g. cervix or oesphagus)
give an overview of the metastasis process
microenvironment of tumour cell is key influential factor in its metastatic ability (to form secondary tumours)
>cancer cell undergoes EMT
intravasion -> circulate -> extravasion -> colonise and undergo angiogenesis
> only 1 in 10,000 cells will set up a secondary tumour
where do tumour cells orignate from?
From a single progenitor cell so all tumour cells are monoclonal cell
why do epithelial tumours make up the majority of cancers?
they are exposed to the environment and many carcinogens (UV radiation)
epithelial cells also have a high turnover and are continuously dividing and replicating so more likely for mutations to occur and mistakes to happen during DNA replication
why are ongogenes easier to detect than defective TS genes?
something that is overexpressed is easier to target
how do growth factors usually signal? how can this lead to cancer?
they can signal through the MAPK pathway by binding to the tyrosine kinase receptor
therefore any GOF of these protooncogenes can lead to sustained proliferation
describe the general mechanism of a growth factor receptor
ligand binds to extracellular domain of tyrosine receptor kinases
results into receptor mediated dimerisations and activates the receptor
trans auto-phosphorylation of the tyrosine residues on intracellular region.
this activated dimer can then activate relay proteins that can dock onto the MAPkinase
transcription of genes involved in cell proliferation and survival
where are cylins and cyclin dependent kinases found in a cell?
they are both found in the cytoplasm. The kinases are always in the inactivated form and usually bound to a repressor protein
once bound to their specific complementary cyclin, they become activated and can phosphorylate target protein and enable next phase of cell cycle to continue
once cyclin is degraded, the CDK returns to its inactivated form
what happens in cancer that affects the cell cycle?
there is a deregulation of checkpoint markers
Overexpression of the proto-oncogene for cyclin D
Loss of TS genes for p16 CDK inhibitor
Loss of TS gene for RB
>HPV can also encode oncoproteon E7 to degrade Rb
in the cell cycle, there are cell cycle checkpoint regulators. Describe one regulator and mechansim of action
Rb is the main regulator for G1->S phase. It is bound to TF E2F.
E2F becomes active when Rb becomes phosphorylated by CDK4/6
how does CDK4/6 become activated? well when cyclin D binds to it and inhibitor p16 dissociated
TF is now free from Rb and can transcribe proteins needed for DNA replication, allowing cell cycle to progress
what can CDK activity be influenced by?
CDK can be inhibited by binding to CDK inhibitors p15, p16 p21 p27
phosphorylation and phosphorylation
binding to its specific cylin!
what is p53?
it is the most important TS gene.
It is a transcription factor and can transcribe genes to put the cell cycle in arrest if the DNA becomes damaged giving time for DNA repair or can initiate apoptosis if DNA cannot be repair
it can become phosphorylated which stabilises it
THEREFORE IF LOF THEN PROMTOTES GENOMIC INSTABLE AND MUTATION ACCUMULATE
what genes can p53 activate
p21 + p27 cylin kinase inhibtios. this will put the cell cycle into arrest, stalling progression allowing time to fix DNA
if cant be fixed, can increase expression of pro-apoptopic molecules like BAX or BAK
what is a common muttion in p53 gene
commonly a SNP in the gene. Hotspots in the DNA binding domain of the TF so p53 cannot perform its function
so the p53, the trancription factor cannot bind to the promoter of DNA and initiate trancription therefore the DNA stays damaged and does not undego apoptosis
Also 50% of p53 mutations are due to methylation. How interesting
what is p53? describe what it does
it is the most important TS gene. it is a transcription factor and can initiate the DNA damage response by promoting apoptosis and transcribe genes to put cell cycle into G1 or G2 cell cycle arrest
> increase in p21 and p27 CDK inhibitors
this allows TIME to fix the DNA. If it cannot be repaired, apoptosis will be initiated
why is p53 a TS gene instead of a caretaker gene
it facilitates DNA damage repair but p53 isn’t actually directly involved in the process of repairing DNA so it merely suppress tumours
