*Pathology (5) Flashcards
What are the 4 cancer causing groups of genes?
Oncogenes - turn these up (cause mutation from photo-oncogene to oncogene)
Tumour supressor genes - turn these off
Turn off genes that stop cells dying = evasion of apoptosis
Break the spell checker genes = allows accumulation of spelling mistakes in oncogenes, tumour suppressors and those that avoid apoptosis (permits progression through the cell cycle even with mistakes)
How does cancer develop?
You need 2 mutations in a gene for cancer to develop (2 hit hypothesis)
Once you have the 2 hits the cells will begin to rapidly proliferate and will accumulate more and more mutations until they become a self sustaining growth
*the 2 it hypothesis refers to tumour suppressor genes
What are the 3 key stages in the development of cancer?
Initiation
Promotion
Persistence
What is initiation?
The 1st mutation is acquired (often in one of the group of 4)
What is promotion?
Further accumulation of mutations
Additive effect
Increased growth
Often results in a “pre-malignant” phase - dysplasia
what is progression?
Cell has developed mutations that allow it to grow in na autonomous fashion
Unregulated abnormal growth
Cells have the ability to invade connective tissue and blood vessels
Malignancy has now been achieved
What are the 3 categories of growth factors?
Receptors with intrinsic tyrosine kinase activity
7 transmembrane G protein-coupled receptors
Receptors without intrinsic tyrosine kinase activity
What is the MAPK/ERK pathway?
a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell
What lesions in the ERK-signalling pathway can cause cancer? (4)
ERGF over expression (most cancers) RAS mutation RAF mutation Myc mutation (we can use "personalised" drugs that specifically target these mutations) *these are all photo-oncogenes
What tyrosine kinase receptors are sometimes mutated in gastrointestinal stromal tumours (GIST) and leukemias?
What therapeutic agent is used to treat this?
C-KIT (growth receptor)
Imatinib
What is RAS?
RAS is a family of related proteins that are involved in transmitting signals within cells
when switched on, RAS turns n other proteins, which ultimately turns on genes involved in cell growth, differentiation and survival
as a result, mutations in RAS can lead to the production of permissively active RAS proteins
(GTP binding proteins)
Proto-oncogene
What type of cancers commonly have RAS mutations? (6)
Colon Lung Pancreatic Bladder Renal Melanoma
What is BRAF?
A downstream of receptor and RAF - it is a photo-oncogene involved in the ERK-signalling pathway
Proto-oncogene
What cancers are associated with (B)RAF?
Melanoma (50% are RAF mutated)
Some colonic malignancies
What is an inhibitor of BRAF that is licensed for melanoma treatment?
Vemurafanib
What is Myc?
A nuclear transpiration factor that promotes growth - DNA replication
Pro-oncogene
What cancers are commonly affected by Myc mutation? (3)
Lymphoma
Neuroblastoma
Small cell carcinoma of the lung
Burkitt lymphoma
What is the most common mutated kinase receptor in cancer?
P13K
What pathway is APC a part of?
Canonical Wnt Pathway
Apart from APC, what other protein in the canonical WnT pathway can become mutated causing cancer?
What cancers is this commonly mutated in?
Beta-catenin
Ovarian cancer
Endometrial cancer
Sarcomas
What does a mutation in JAK2 commonly occur in?
Haematological malignancies
What type of proteins are often prefixed with “p”?
Tumour supressor genes
What is the most commonly mutated protein across all cancers?
p53 - tumour supressor gene
What does p53 do?
Senses DNA abnormalities at G1 and pauses the cell cycle - increases levels of p21 which is a CDK inhibitor
If DNA is repaired, p53 restarts the cell cycle
If repair is not possible, p53 initiates apoptosis
What is CDK activated by?
Cyclins
What cycle does p53 initiate apoptosis by?
BAX cycle
What Von-Hippel Lindau disease?
a disease which results from a mutation in the von Hippel–Lindau tumor suppressor gene which causes multiple tumours to develop (mostly renal cancers)- loss of a functioning VHL gene increases levels of angiogenic growth factors
What does PTEN do?
Increased transcription of p27 - p27 blocks CDKs and cell cycle progression and therefore inhibits P13K/AKT pathway
Therefore a mutation in this causes proliferation in an uncontrolled manner
What are 4 examples of DNA repair genes?
MLH1, MLH2, PMS1, PMS2 - mutations in these can lead to the likes of HNPCC and Muir Torres
What parts of DNA do DNA repair genes specifically look at?
Microsatellite regions
What type of genes is BRCA?
DNA repair genes/ tumour supressors
What types of cancers do BRCA mutations increase your risk of?
Breast
Ovarian
Pancreatic
What genes are involved in evasion of apoptosis and how?
p53 and BCL2
p53 increases levels of BAX
BAX stops BCL2
BCL2 is anti-apoptotic
Is Bcl2 pro or anti-apoptotic?
Anti-apoptotic
Is Bcl2 normally on or off in normal lymph node follicles?
Off - need apoptosis to get rid of self reactive lymphocytes
How do many lymphoma cells avoid apoptosis?
By switching on BCL2
