L18: Basic Molecular pathology Flashcards
What are two methods for removing tissue from a lung?
Bronchoscopy–> Camera into airways–> bronchus–> into lung–> take small piece of tumour
CT guided biopsy–> Needle inserted into lesions using CT scan as guide–> remove some of lesion
What are the lung molecule markers that are looked for?
PDL1 EGFR Kras BRAF MET Ros1 ALK All markers of adenocarcinoma Certain mutations lead to certain types of cancers
What are the causes of lung adenocarcinomas?
2/3 mutation in oncogenes
1/3 tumour suppressor genes (p53 and Rb)
What sort of oncogenic mutations can occur?
MET, (KRAS, EGFR, BRAF, HER2, PIK3CA) mutations
ALK, ROS1 (RET), gene rearrangements
What sort of tumour suppressor mutations can occur?
p53 mutation is seen in 50% of NSCLC and 80% small cell lung cancers
What are immunotherapies?
Type of treatment designed to boost the bodies defences
Give an example of an immunotherapy used?
Inhibit PDL1 (programmed death) ligand (high on cancer cells so can usually trick the immune system and avoid being attacked) or its receptor
Using monoclonal antibodies
Reverse T cell exhaustion and results in activation of host anti-tumour immune response
Nivolumab/ Pembrolizumab against PD-1 R
Atezolizumab and Duralumba against PDL1 (ligand)
How do cancer cell remain alive?
Mutation in
- Proto-oncogenes to oncogenes so results in proliferation
- Mutate Ts genes (double hit)
1. Overexpress anti-apoptotic factors–> inhibit apoptosis
2. Inhibit pro-apoptotic signals –> p53 and caspases–> uncontrolled proliferation, no repair if DNA damaged
3. Over express growth factors and/or growth factor receptors
4. Mutate DNA repair mechanisms (MLH and MSH)
How do growth factors increase cancer survival? Give examples of some growth factors?
Growth factors help the cells stay alive and proliferate
Low requirement for growth factors (don’t need much to produce a response)
PDGF–> platelet derived growth factor–> angiogenesis and stromal proliferation
TGF beta–> transforming growth factor–> angiogenesis, interaction with lymphocytes and macrophages (supress immune system response) and production of extracellular matrix
What growth factor receptors can lead to cancer formation?
Tyrosine kinase receptor–> EGFR, c-erb B2
EGFR expressed on epithelial cells: amplified and thus overexpressed in lung SqCC, Adenocarcinomas and breast cancers
ERB B2–> R gene amplification and overexpressed–> breast cancers
What can be used to treat cancers caused by over expression on EGFR?
Anti EGFR drugs such as afatinib, gefitinib, erlotinib (all the -tinibs)
What drug is used to treat cancers caused by ERB B2?
Herceptin
What targetted drugs do we have for lung adenocarcinomas?
Anti EGFRs, anti ALK, anti B-Raf
Why are lymph nodes looked at?
To see if the tumour has metastasised to anywhere
Lymph nodes because of lymphatic drainage
Lymph nodes can be removed
What is used to detect a melanoma?
A- asymmetry–> is it asymmetrical?
B- border–> does it have a irregular border?
C- colour–> is it all one colour
D- diameter–> how big is it?
E- evolution–> has it evolved? over how long?
What markers are commonly seen in melanomas?
Most melanomas:
NRAS (15%) and BRAF (45%) (V600E)
leads to activation of MAPK pathway (mitogen activated protein pathway)
Different ones for mucosal melanomas and acral (hand and feet)
How do BRAF and NRAS lead to melanoma?
Part of MAPK (mitogen activated protein kinase pathway)
NRAS activates BRAF
BRAF activates signalling pathway (MEK) leads to transcription of DNA –> cell proliferation and survival
What treatments are available for BRAF and NRAS melanomas?
Anti BRAF–> Dabranfenib, Tramtinib
Inhibit BRAF preventing activation of pathway
However tumour resistance can develop on 6 months on selective BRAF inhibitors alone
What immunotherapies are used to treat melanomas?
Disease lacking BRAF mutation
PD-1 (receptors) binds to PDL1 (ligand) –> inhibits T cell proliferation meaning T cells can’t destroy cancer cells
PDL1 widely expressed on tumour cells
Block PDL1 ligand from binding to receptor–> T cells can restore normal function
Increase cytokine production
Cytolyisis of cells
What medications are prescribe as immunotherapies?
Nivolumab and Pembrolizumab (Againt PD1- R)
What other cancers are also developing personalised treatments?
Metostatic urothelial carcinoma - PDL1
Colorectal cancer- DNA mismatch repair enzymes
