Cancer Flashcards
Name 3 differences between cancerous and non-cancerous cells?
Cancerous - abnormal morphology, dysregulated growth, loss of contact inhibition
Non-cancerous cells, standard morphology, organised monolayer, have contact inhibition
What is a proto-oncogene and what are its main roles?
It is a normal cellular gene. It codes for ‘oncoprotein’ that are
important for stimulating cell growth and differentiation!!!
- regulates transcription
- growth factor signalling
- INHIBITS APOPTOSIS
When proto-oncogenes acquire mutations they are called? Give some examples
Oncogenes
- Cytokine/growth factor: e.g. EGFR
- Transcription factor: Myc
- Signalling kinase: Src
- anti-apoptotic factors - Bcl
In what ways can protooncogenes acquire mutations?
- Gain of function mutations: when very specific mutations are involved
- Dominant effect: only one copy of the gene needs to be mutated to elicit and effect
Name some some specific mutational mechanisms of proto-oncogenes
Point mutations e.g. KRAS
Amplification e.g. N-MYC
Translocation e.g. BcR-AbL
What is KRAS? What is its role in normal cell function? What happens when it is mutated?
KRAS - member of the RAS family, type of proto-oncogene
- important for normal proliferation, differentiation, senescence
In GTP - bound state: ACTIVE: signals growth and inhibition of apoptosis
In GDP - bound state: INACTIVE:
KRAS mutations, are dominant point mutations.
It causes KRAS to be stuck in the GTP bound state by blocking the intrinsic GTP activity.
What is N-MyC? What is its role in normal cell function? What happens when it is mutated?
N-MyC, proto-oncogene. It is a transcription factor. Primarily expressed in EMBRYOS. - Critical in brain and neural development.
- promotes division of neuron progenitors
When it is mutated: It is amplified/over-expressed and can cause neuroblastoma.
What is Bcr and Abl involved in during normal cell function?
ABL - it is a tyrosine kinase, involved in differentiation, division, adhesion
BCR - serine/thereonine kinase, involved in cell signalling
What happens during Bcr-Abl translocation?
The Bcr and Abl gene fuse together on chromosome 22 ‘Philadelphia chromosome’.
- It dysregulates the tyrosine kinase function
- acts as active growth hormone receptor ===> driving myeloid proliferation
FOUND IN CHRONIC MYELOID LEUKEMIA (CML)
How can you therapeutically target BcR-Abl translocation?
a) inhibits the tyrosine kinase activity
b) Imatinib mesylate - binds competitively to bcr-abl and inhibits the protein
What is a tumour suppressor gene (TSG)? Give some examples
TSGs STOP cell growth, THEY KEEP THE CELL IN CHECK. Activate apoptosis, block cell cycle from continuing, respond to damaged DNA.
- cell cycle regulation e.g. RB1
- DNA damage checkpoints and apoptosis e.g. TP53 (p53)
- cell adhesion signalling e.g. APC
- DNA Repair e.g. BRCA1
What type of mutations do tumour suppressor genes acquire?
Loss of function mutations: many different types of mutations are involved
and Recessive effect: both versions of the gene need to be mutated
OFTEN IN FAMILIAL CANCERS
Name some some specific mutational mechanisms that inactivate tumour suppressor genes
point mutations e.g. change a codon
deletion/insertion
inversions
methylation
however remember it requires both genes to be inactive to cause uncontrolled growth
What is a Loss of Hetrerozygosity (LOH)?
Generally occurs in TSG mutations.
A POINT mutation in one allele followed by DELETION of the other allele.
RB1 is a type of TSG, what kind disorder can it cause?
Retinoblastoma
cancerous tumour of the retina
bilateral - if it is an inherited mutation
unilateral - if it is a sporadic mutation
What is p53? why is it important? what happens when it is mutated?
p53 is the “gatekeeper” of tumour suppressor gene
It is:
a) transcription factor
b) cell cycle check point protein (G1 to S phase -do we want to replicate the DNA?)
c) DNA damage mediated apoptosis
If a person only inherits one functional copy of the p53 gene, and the other one has an inactivated mutation - the normal copy will be lost ==> can develop Li-Fraumeni syndrome in adulthood
Explain the difference between sporadic (acquired) vs inherited (familial) cancer
Sporadic - occurs in the somatic cell
- mutations dont often happen in the genes but they occur all the time in cells
- takes a long time to happen
- generally have a later onset in life
Inherited - occurs in the germ line cell
- if its the TSG that has the mutation, the second copy of the gene will quickly get the mutation also
- activated mutations of oncogenes are usually embroyanically lethal so its not usually inherited
- early onset, usually TSGs
How do viruses cause cancer?
Viruses can cause cancer by acting as oncogenes.
They insert viral oncogenic genes into the host cell, affect the existing porto-oncogenes and block the function of TSGs
e.g. human papilloma virus causing cervical cancer
Explain underlying mechanisms in colon cancer
Normal epithelium — (LOSS OF APC gene) —–> Hyper proliferation of epithelium —> Early adenoma “benign tumour of the glandular epithelium” —– (ACTIVATION OF THE KRAS GENE) —-> Intermediate adenoma —- (LOSS OF THE DCC Gene/chromosome 22) —> late adenoma — (LOSS OF p53 gene) —-> Carcinoma — (OTHER ALTERATIONS) —-> Metastasis
What are the colon risk factors (%) of familial vs sporadic?
20% familial
30% due to nutrition of high fats, meat, high BMI etc
What are the 6 hallmarks of cancer?
- Proliferation signalling
- Cell Death resistance
- Angiogensis
- Metastisis/Invasion
- Replication immortality
- Evade from growth suppressors
What is Familial adenomatous polyposis (FAP)? What is caused by?
Autosomal dominant, pre-malignant disease that usually progresses to malignancy. Causes innumerable polyps – CAUSED BY APC gene
What is APC?
APC - adenomatous polyposis coli gene
- encodes a tumour suppressor protein
- The protein made by the APC gene plays a critical role in several cellular processes that determine whether a cell may develop into a tumor.
- inactivation of APC. When APC does not have an inactivating mutation, frequently there are activating mutations in beta catenin.
- Mutations in APC or β-catenin must be followed by other mutations to become cancerous; however, in carriers of an APC inactivating mutation
What are stability genes?
- normally function to repair error of DNA replication or those cause by outages
- When they are inactivated, errors slowly accumulate
- produces expansions and contractions of micro satellite DNA sequences, tandem repeats of nucleotides leading to “micro satellite instability”
What is hereditary non-polyposis (HNPCC) caused by?
inherited mutation of mismatch repair genes
in brown nuclear staining, MMR (mismatch repair) protein should be present
