1. introduction and nomenclature Flashcards
when work is done on model organisms, what is needed to be done with the data?
it needs to be extrapolated back and made relevant to humans
what is cancer?
a group of diseases generally characterised by genomic instability and uncontrolled cell division and leading to invasion of surrounding tissue and eventually dispersal to different sites
what does this general description of cancer not take into account?
fluid tissues i.e. blood cancer
there are over 200 different clinical classifications of cancer, what does this equate to?
200 cells types of the body
what are the four biggest cancer killers?
breast cancer
lung cancer
large bowel cancer
prostate cancer
what percentage of cancer mortalities are due to lung cancer? and what is this almost entirely due to?
14%
smoking
why is colon cancer so prevalent?
this is a highly proliferative tissue
give a reason that cancer is so hard to treat
no two cancers are the same
name the type of cancer that arises in the epithelial layer and what percentage of cancers arise here?
carcinoma
90%
name they type of cancer that arises in the connective tissue and bone (non-epithelial tissue)
sarcoma
name the type of cancer that arises in plasma cells
myeloma
what is leukaemia and what does it affect?
blood cancer that arises in the bone marrow and can affect circulation
what is a mixed tumour? and how is it diagnosed?
this is a tumour that is derived from multiple tissues, it is diagnosed by looking at histological samples
what is a risk factor for cancer? and why is this?
age, genome accumulates mutations throughout life
what is amazing about how many cells there in our body and what does this show?
all 10^4 cells in our body arose from a single cell, given the number of cell divisions and DNA copied its amazing we don’t get more cancer. this shows that we have good replication and repair machinery in place.
give four factors that can contribute to mutations arising in our genome?
- exposure to radiation or carcinogens
- hereditary disposition
- DNA damage by ROS
- viral infection
name two types of genes that if mutated give rise to genomic instability?
tumour suppressers and oncogenes
what is a tumour suppresser and what has to occur for it to promote cancer formation?
a tumour suppresser is a gene that prevents cancer from occurring, when mutated it loses its function
what is an oncogene and what has to occur for it to promote cancer formation?
an oncogene is a gene that when it functions abnormally, promotes tumour growth, when a proto-oncogene is mutated it has a gain of function and becomes oncogenic
what type of gene mutation makes a more easy therapeutic target?
oncogene, as you cannot target something that is not there i.e. a lost tumour suppresser
what did Peyton Rous see in 1911? and what was he the first person to recognise?
he saw that sarcomas were transmissible between chickens, he used cell free tumour extract to infect chickens and saw them develop tumours, showing an inheritable basis for this type of tumour
he recognised the presence of oncogenes
what retrovirus was Peyton Rous infected his chickens with?
Rous Sarcoma Virus
describe the genome of a retrovirus
relatively small RNA genome
what is at either end of the retroviruses genome?
at either end of the genome there are long terminal repeats (LTRs) so that the virus can insert itself into the host genome.
what are the genes encoded for by a retrovirus genome?
ENV - encodes envelope genes
POL - encodes reverse transcriptase (makes DNA from RNA for insertion into host genome)
GAG - encodes capsid proteins to protect genome from environment
what is the additional gene found in RSC that will lead to cancer? and what type of gene is this?
vSRC
it is a transforming gene because it is able to turn normal cells into cancer cells
what is the difference in sequence between vSRC and cSRC? and what does this difference mean?
cellular SRC has an extension at the C terminus and a substitution mutation of glutamine to phenylalanine
this difference accounts for the fact that vSRC is transforming and cSRC is not
name the domain that binds phosphotyrosines
SH2
name the domain that binds proline rich sequences
SH3
from N to C terminus list the domains and important features of SRC
SH3, SH2, kinase domain, Tyrosine 527
what type of kinase domain does SRC have and what does it do?
tyrosine kinase that transfers gamma phosphate of ATP onto tyrosine
describe the inactive form of SRC?
- SH2 binds phosphotyrosine 527
- SH3 bind proline rich domain between SH2 and SH1.
- this squeezes catalytic domain shut and so stops substrate from binding
what form is cSRC normally found it?
inactive, but can be switched on if needed
why cant vRSC be inactivated?
it lacks the C terminal Tyrosine 527 and so is constitutively active
name 4 retroviral oncogenes and what type of protein are they?
Src - tyrosine kinase
Ras - GTPase (constitutively active)
Fos - transcription factor (lacks P site for nuclear exclusion)
Sis - platelet derived growth factor (growth factor constantly expressed)
what are the cellular version of these viral oncogenes?
proto-oncogenes
what type of mutations may make a proto-oncogene oncogenic? (4)
- point mutation
- truncation
- gene amplification
- chromosomal translocation
what is the most commonly mutated gene in human cancer? and define the most common mutation
Ras
conserved glycine mutated to valine
what are many cancers initiated by? these are most common in tumours, how does this have an effect on therapies?
loss of tumour suppresser
you cannot drug something that is not there
describe the Knudson’s two hit hypothesis
in order to inactivate a tumour suppresser, two genetic mutations need to occur. mutations can be sporadic or familial. in the case of sporadic, two somatic mutations need to occur. in the case of familial, only one somatic mutations needs to occur as the first is inherited.
who was knudson and what did he do?
he was a surgeon that look at the pedigree of retinal cancer and formed a hypothesis on tumour suppressers based on classical genetics
how many mutation need to occur to activate an oncogene and how it this different for tumour suppresser?
one
two mutations need to occur to knock out TS function
how do sporadic and familial tumour suppresser losses differ in terms of when and what type of tumour formations occur?
- sporadic tumour are late onset and single tumour
- familial tumours are early onset and multiple tumours
once the first hit is occurred and chromosomes are heterozygous, what needs to happen for a loss of TS? and when this happens at a certain location what it this an indictor of?
loss of heterozygosity at a certain location is an indicator of a TS
why is only one mutation in oncogenes enough to drive cancer?
even through you have one WT copy of the gene still, you have one constitutively active copy that will drive cancer
whats the difference between the difference types of mutations that can lead to loss of TS and gain of oncogene?
many different types of mutations can occur in order to lose an oncogene, but define mutations have to occur to generate an oncogene
