Carcinogenesis 2 Flashcards
define darwinian evolution and clonal expansion of the intent mutant
clonal expansion of the initiating mutant, in order that it will acquires 2nd mutation.
define caretaker gene
maintain genetic stability by repairing damaged DNA and replication errors and controlling the accuracy of mitosis.
what feature of tumour cells can mutation in a caretaker gene cause
genetic instability.
what type of genes are caretaker and gate keeper genes
tumour suppressor genes
define gatekeeper gene
negative regulators of the cell cycle and proliferation.
positive regulators of apoptosis.
positive regulators of cell differentiation.
do both tumour suppressor genes have to be hit in order for inactivation
Yes.
how can the promoter region of tumour suppressor genes be inactivated
hypermethylation of the CpG islands.
define epigentic silencing
hypermethylation of the CpG islands (promoter region)
what is typically the cause of the 1st hit in tumour suppressor genes
single point mutation.
what is typically the cause of the 2nd hit in tumour suppressor genes
chromosomal non-disjunction (leads to aneuploidy)
Chromosomal recombination- takes place in meiosis as it combines maternal and paternal genetic material. However in somatic cells during mitosis it can create a daughter cell that is homozygous for the first mutation in TSG.
what is the most common feature of tumour cells
aneuploidy- daughter cells have the wrong amount go chromosomes.
how do familial cancers predispose individuals with a greater risk of developing a cancer
inheritance of a mutant copy of a gatekeeper or caretaker gene, so only require 1 hit to be classes as cancer.
what gene is involved in retinoblastoma and is it a gate keeper of caretaker
gatekeeper
RB1
what gene is involved in Li- Fraumeni and is it a gate keeper of caretaker
p53
gate keeper and care taker
what are the principal tumours in Li fraumeni
sarcomas and breast
what gene is involved in familial adenomatous polyposis and is it a gate keeper of caretaker
APC
Gate keeper
what are the principal tumours in familial adenomatous polyposis
colorectal
what gene is involved in familial breast cancer and is it a gate keeper of caretaker
BRAC1/BRAC2
caretaker
what are the principal tumours in familial breast cancer
breast and ovarian
what gene is involved in hereditary non polyposis colorectal cancer and is it a gate keeper of caretaker
hMLH1, hMSH2
care taker
what are the principal tumours in hereditary non polyposis colorectal cancer
colon endometerial
define proto-oncogenes
promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis
define oncogenes
mutations lead to activated versions or increased expression of proto-oncogenes – GAIN OF FUNCTION
how many mutant oncogene do you need to induce gain of function
one- the mutated gene is dominant.
what mechanisms activate oncogenes.
Translocation of a proto-oncogene from a low transcriptionally active site to an active site - aberrant expression of the oncogene.
E.g. moving the gene to where immunoglobulin’s are present as they are expressed transcpitionally a lot.
Point mutation - substitution of a single base pair can alter an amino acid in the protein causing it to become hyperactive
Amplification by insertion of multiple copies of an oncogene – increased expression.
what is the minimum number of genetic alternations required to transform a normal cell into a neoplastic cell
3
stage by stage tumorigenesis of colorectal cancer.
normal epithelium- loss of APC
Hyperplastic epithelium- DNA hypomethylation.
early (activation of K ras)- intermediate(loss of 18q TSG) - late adenomas
loss of p53- carcinoma
invasion and metastases.
do tumour cells require a stimulus of positive growth factor before they enter the cell cycle and divide
NO
define signal transduction (process used to inform cells whether they need to enter the cell cycle )
passage of signals from outside the cell, through the almost impervious cell membrane, across the cytoplasm and into the nucleus, where changes in gene expression can take place
what factors carries signals about whether a cell needs to enter the cell cycle or not
growth factor
where are growth factor receptors located
on the cell membrane of cells.
what is the function of growth factor receptors
stimulate a cascade of signalling events that culminate in the nucleus with changes in gene expression.
how do oncogenes manipulate RAS in order to continue cell division and proliferation
cancer cells carry an activated RAS oncogene mutation where they alter 1 amino acid involved in the cleaving of the phosphate group from GTP. This means that once the RAS oncoprotein has acquired a GTP molecule and shifted into its active state it is unable to revert back to an inactive state
do cancer cells respond to negative growth factors which inform cells to leave the cell cycle
No
what is the function of RB protein
key regulator of cell cycle by preventing progression from G1 to S phase.
how to tumours prevent responding to negative growth factors
Inactivation of RB gene.
in a non proliferating cell what is the function of RB
in a non proliferating cell does the RB bind to and suppress the activity of transcription factors whose function is to switch on genes required for proliferation
In a proliferating cell cell what is the function of RB
retinoblastoma protein is phosphorylated, and therefore inactivated, by kinase enzymes that have been switched on via a proliferation signal transduction pathway
what negative growth factor activates RB and how does it activate RB
transforming growth factor beta (TGFbeta).
stimulating the expression of proteins that inhibit the kinase enzymes that inactivate RB
what enzymes inactivate RB
kinase
when RB is phosphrylated is it active or inactive
inactive
do tumour cells have a finite replicative ability before they become senesce and die due to loss of telomeres
No
how to tumour cells have a infinite replicative ability
Tumour cells express telomerase that replaces the lost material and cells become immortal.
what is the function of telomerase
maintain telomere length.
what are the telomeres made of
Thousands of repeats of hexanucleotide sequence
what is the 6 base composition of the telomere hexanucleotide sequence
TTAGGG
due toe a defiecncy in DNA replication process what is lost every time you replicate DNA
part of the telomere.
what happens to cells when all the telomere has been lost after numerous replications
chromosomes become exposed and are able to fuse with each other resulting in karyotypic chaos, which usually triggers apoptosis
how does telomerase replace lost telomeres
using an RNA template.
when is telomerase typically expressed in normal human cells
embryogenesis but expression is lost in cells once they differentiate
how do tumour cells resist apoptosis
P53 induces cell cycle arrest to allow repair of DNA damage
But also induces apoptosis if too much damage
TP53 inactivation leading to loss of apoptotic response is the most common genetic abnormality in human tumours
what gene is involved in apoptosis
p53
what size tumours need a blood supply
> 2 mm
what is the name of the transcription factor which induces VEGF, and what causes the transcription factor to be stimulated
HIF-1 transcription factor
hypoxia
what is the function of VEGF
construct new capillaries and vessels
actively recruit endothelial cells that proceed to construct new capillaries and vessels
Can malignant cells invade other tissue and detach from their own
Yes
what holds cells together
E cadherin
how does e cadherin become inactivated in genes
mutation/hypermethylation of the gene
what is epithelial mesenchymal transition
Mesenchymal cells are motile and secrete proteases - allows them to break through basement membrane and invade the underlying stroma
what is the clinical application of tumour markers
screening diagnosis prognosis therapy monitoring
example of a tumour marker which is predictive for prognosis.
- Gene expression profiling of acute myeloid leukaemia (AML) subtypes
- AML subtypes with different translocations (t(11q23)/MLL, t(8;21), t(15;17), inv(16), and AML with complex aberrant karyotypes) are clearly distinguished based on differential genomic expression from 749 probe sets
example of a tumour marker which is a predicitve marker for therapeutic response.
- HER2 (erbB2/neu) codes for a +ve growth factor receptor
- Overexpression found in ~30% of breast tumours (gene amplification)
- Makes cells more responsive to, or independent of, +ve growth factors
- Herceptin is an antibody drug targeted to HER2 and dampens the effects of an overactive HER2 receptor
- Only patients with HER2 overexpression have Herceptin treatment as individuals without overactive HER2 receptors will have no beneficial effect
