Neoplasia III Flashcards
4 groups for cancer?
Turn up genes that promote growth - oncogenes
Turn off genes that slow growth - tumour suppressor genes
Stop cell death - evasion of apoptosis
Break the spell checker - allows accumulation of spelling mistakes in oncogenes, tumour suppressors and those that evade apoptoses (permits progression through cell cycle even with mistakes)
Describe the first mutation in cancer development
Should be one of the 4 groups. usually an oncogene, tumour suppressor, DNA repair or evasion of apoptosis
Describe further mutations
Need more than 1 mutations for cells to proliferate; more mutations = increased growth , eventually leading to a self-sustaining growth (cancer)
Stepwise progression in different cancers?
Some steps are important first steps and are often predictable in certain tumour types:
APC mutation in sporadic colon cancer
Steps in cancer development?
Initiation - 1st mutation acquired
Promotion - further accumulation of mutations lead to increased growth and often results in pre-malignant phase (DYSPLASIA)
Persistence - mutations allow cell to grown in autonomously and there is unregulated abnormal growth; cells also have ability to invade connective tissue and blood vessels (MALIGNANCY)
Stepwise progression of colon cancer?
Reasonably predictable steps:
Initiation - APC mutation
Promotion - KRAS
Persistence
Describe oncogenes in cancer
Cells receive growth promoting signals - physiological
Signalling pathway is frequently altered in cancer and cells receive uncontrolled growth signals
3 categories of growth receptors?
- Receptors with intrinsic tyrosine kinase activity
- 7 transmembrane G-protein coupled receptors
- Receptors without intrinsic tyrosine kinase activity
Describe the MAPK/ERK pathway
Normal MAPK/ERK pathway - EGF (Epidermal Growth Factor) binds to the receptor (EGFR) and begins a reaction involving RAS, RAF and other molecules and eventually MYC, which promotes transcription
In cancer - there can be (all steps are often mutated in cancer):
EGFR over expression (>50% adenocarcinomas) - many tumours have this mutation
RAS mutation
BRAF mutation - one of three RAF proteins found in mammals
Action of herceptin?
Targets EGFR
Drugs targeting EGFR?
Trastuzamab (Herceptin)
Erlotinib
Cetuximab
No point targeting EGFR if mutations further downstream
Drugs targeting RAF?
Sarafenib
Geldanamycin
Drugs targeting MEK?
Trametinib
Refametinib
What is C-KIT?
Receptor tyrosine kinase that is mutated in GI stromal tumours (GIST) and leukaemias
Imatinib is a common therapeutic agent
Describe RAS proteins
KRAS, HRAS and NRAS
All GTP-binding
Mutated in colon, lung, pacreatic, kidney, renal cancers and in melanoma
Inhibitors are licensed for use in melanoma
Describe BRAF protein
Downstream of both receptor and RAS
50% of melanomas have RAF mutations
Some colonic malignancies involve RAF mutations, not APC
Inhibitors are licensed for melanoma treatment - Vemurafanib
What is MYC?
One of the last points in the sequence - it is a NUCLEAR TRANSCRIPTION FACTOR that promotes growth, DNA replication, etc
Mutated commonly in lymphoma, neuroblastoma, small cell carcinoma of lung
Describe the MYC gene in Burkitt’s lymphoma
MYC gene is broken apart (abnormal)
MYC translocation is diagnostic in Burkitt’s lymphoma
Most commonly mutated kinase in cancer?
PI3K - mutations lead to:
Increased protein synthesis and cell growth
Cell cycle progression/proliferation
Survival/decreased apoptosis
Treatment for PI3K mutations?
Limited success intrials
Targeted at haematological malignancies, e.g: chronic lymphocytic leukaemia
May be used in combo with receptor inhibitors
Describe normal 7 transmembrane G proteins
G-protein coupled receptors are responsible for a wide range of physiological response and are often targets of pharmacological agents
Describe the normal canonical Wnt pathway?
bind to G-protein coupled receptor (7 transmembrane proteins)
Activates other molecules like APC and β-catenin (promotes transcription
Mutations in canonical Wnt pathway?
APC mutation - one of the earliest mutations in colorectal cancer and can occur as a germline mutation, causing an inherited condition (Familial Adenomatous Polyposis and Gardner’s syndrome)
β-catenin mutation - in ovarian cancer, endometrial cancer and in sarcomas
PTCH mutations?
In skin cancers - basal cell carcinoma Gorlin's syndorme Odontogenic cysts (in jaw) and BCCs (Basal Cell Carcinomas)
