cancer

Question 1

what are the typical patterns of mutations for a proto-oncogene compared to a TumorSupressor gene? (how can we distinguish a

Answer 1

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

Question 2

how does cancer relate to aging?

Answer 2

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

Question 3

which type of cancer is makes up 1.5% of all cancers?
A sarcoma
B carcinoma
C lymphoma/leukamia
D neuroectodermal

Answer 3

OPTION D - neuroectodermal

80% carcinoma
1% sarcoma
7% leukiamea

Question 4

what is dysplasia?

Answer 4

tissue that is in a pre-malignant state
> hyperchromatic nuclei
> lacks differentiation markers
> looks abnormal

Question 5

describe how myeloid leukaemia can develops

what actually causes the onset of ML?

Answer 5

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

Question 6

what are driver and passenger mutarions

Answer 6

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

Question 7

karyotype and cancer

Answer 7

cancer cells have abnormal karyotypes which promote genomic instability
> aneuploidy +- or polyploidy (duplicaton)
> translocations
> deletions
> chromothrispis

Question 8

what is chromospthrispis? what is consequence of chromothripsis in cancer?

Answer 8

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

Question 9

where do cancer cells derive from

Answer 9

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

Question 10

why do cancer cells show heterogeneity within a tumour mass if they are genetically identical?

Answer 10

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

Question 11

what are key differences between normal and cancer cell

Answer 11

~~~
cancer cells can
> be migratory (via EMT) lack polarity
> lack differentiation markers
> hyperchromatic and multi nucleic
> look abnormal

Question 12

what results in formation of proto-oncogene

Answer 12

1. qualitative: formation of abnormal protein due to SNP or translocation = fusion protein/ strong promoter (22:9), or even virus oncoproteins
2. 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

Question 13

how can a LOF of a TS gene occur ?

Answer 13

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

Question 14

what is a TS gene? can you name some examples?

Answer 14

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

Question 15

how can we detect these driver mutations

Answer 15

use large scale genomic sequencning

Question 16

what do proto-oncogenes do? how does it achieve its function?

Answer 16

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

Question 17

what is cancer?

Answer 17

refers to a malignant neoplasm/tumour

this can metastasize and invade cells, appears abnormal

Question 18

cancers can be classified according to their (tissue) origins. Name the 4 subtypes

Answer 18

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

Question 19

give an example of how a benign tumour can evolve into a cancer

Answer 19

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

Question 20

name some of the ESTABLISHED hallmarks of cancer

Answer 20

excessive cell proliferation
can evade the growth inhibitory signals
can evade apopotosis/cell death
are replicatively immortal
induce angiogeneisis
can undergo metastasis and invasion

Question 21

name the cellular changes that distinguish cancer cell from a normal cell

Answer 21

enhanced stimulation of growth factors
hyperplastic , metaplastic
Poorly differentiated
Looks abnormal
multilobed nuclei

Question 22

what is the difference between a benign and malignant neoplasm?

Answer 22

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

Question 23

define hyperplastic and metaplastic

Answer 23

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)

Question 24

give an overview of the metastasis process

Answer 24

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

Question 25

where do tumour cells orignate from?

Answer 25

From a single progenitor cell so all tumour cells are monoclonal cell

Question 26

why do epithelial tumours make up the majority of cancers?

Answer 26

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

Question 27

why are ongogenes easier to detect than defective TS genes?

Answer 27

something that is overexpressed is easier to target

Question 28

how do growth factors usually signal? how can this lead to cancer?

Answer 28

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

Question 29

describe the general mechanism of a growth factor receptor

Answer 29

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

Question 30

where are cylins and cyclin dependent kinases found in a cell?

Answer 30

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

Question 31

what happens in cancer that affects the cell cycle?

Answer 31

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

Question 32

in the cell cycle, there are cell cycle checkpoint regulators. Describe one regulator and mechansim of action

Answer 32

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

Question 33

what can CDK activity be influenced by?

Answer 33

CDK can be inhibited by binding to CDK inhibitors p15, p16 p21 p27 phosphorylation and phosphorylation binding to its specific cylin!

Question 34

what is p53?

Answer 34

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

Question 35

what genes can p53 activate

Answer 35

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

Question 36

what is a common muttion in p53 gene

Answer 36

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

Question 37

what is p53? describe what it does

Answer 37

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

Question 38

why is p53 a TS gene instead of a caretaker gene

Answer 38

it *facilitates* DNA damage repair but p53 isn't actually directly involved in the process of repairing DNA so it merely suppress tumours