Cancer Genomics Flashcards
What are the three classifications of germ line DNA changes?
VariantMutationPolymorphism
Define polymorphism
= variant not causing disease
Define mutation
= variant causing disease
Define variant
= any change from the reference DNA sequence
What are the three classifications of cancer DNA changes?
somatic mutation (variant)driver mutationpassenger mutation
Define somatic mutation (variant)
= any change from the patient’s germ line DNA sequence
Define driver mutation
= somatic mutation contributing to cancer development
Define passenger mutation
= somatic mutation not contributing to cancer development
What are the small scale nucleotide sequence changes called?
Point mutationInsertion or deletion
What are the large scale nucleotide sequence changes called?
TranslocationAmplificationInsertion or deletion
What is the DNA change in epigenetic changes?
Promoter methylation
Genes involved in cancer are either..?
- Oncogenes or 2. Tumour suppressor genes
What are oncogenes?
Gene function promotes cancer formationMutations causes increased gene functionMutations are dominant (only one allele mutated)
What are TSGs?
Gene function normally inhibits cancer formationMutations cause loss of gene function or expressionMutations are recessive (both alleles must be knocked out)
What is a driver mutation?
Driver mutation drive the tumour and contribute to cancer dvpmtInvolve oncogenes and TSGConfer advantage in growth or survival, therefore are positive selected(5-10 driver mutations per cancer?)
What are passenger mutations?
Mutations that do not confer any advantage (along for the ride) Just happens to be in the same cell as the driver mutations(1000-100,000 passenger mutations per cancer)
What is a driver mutation?
Driver mutation drive the tumour and contribute to cancer dvpmtInvolve oncogenes and TSGConfer advantage in growth or survival, therefore are positive selected(5-10 driver mutations per cancer?)
What is the MAPK signalling pathway in cancer?
Hallmark: sustained proliferative signallingKey genes: - EGFR (growth factor receptor)- HER2 (growth factor receptor)- (K)RAS- (B)RAF
What is HER2?
HER2 is a growth factor receptor which signals via the MAPK pathway (and other pathways)App. 20% of breast cancers have HER2 gene amplification i..e more growth factor receptors on the cell surface
Which drug targets the HER2 receptor in breast cancer?
Trastuzumab - monoclonal Ab that interferes with HER2 function and/or induces immune destruction of cells baring HER2*monoclonal Ab act on the cell surface
What is BRAF V600E?
BRAF is an important protein in the MAPK pathway.BRAF V600E is a mutation seen in 50% of melanomas that causes constitutive activation of MAPK signalling
Which drug targets V600E mutant BRAF?
Vemurafinib - small molecule inhibitor of V600E mutant BRAF*a small molecule inhibitor means that it acts in the cytoplasm
What is EGFR?
Growth factor receptor which signals via the MAPK pathway (and other pathways)15% of non-small cell lung cancers (NSCLC) have activating EGFR mutations
What drugs target EGFR?
Gefitinib and erlotinib: small molecule EGFR inhibitors
What is BRAF V600E? What disease is commonly associated with?
BRAF is an important protein in the MAPK pathway.BRAF V600E is a mutation seen in 50% of melanomas that causes constitutive activation of MAPK signalling
What is EGFR? What disease is commonly associated with this mutation?
Growth factor receptor which signals via the MAPK pathway (and other pathways)* 15% of non-small cell lung cancers (NSCLC) have activating EGFR mutations * EGFR is expressed in most colorectal cancers
What drugs target EGFR in non-small cell lung cancers?
Gefitinib and erlotinib: small molecule EGFR inhibitors
What drugs target EGFR in colorectal cancers?Which patient group does not respond to this drug?
Cetuximab: monoclonal Ab that inhibits EGFR function*patients who have tumours that have activating KRAS mutations DO NOT respond to cetuximab (even if they have EGFR) therefore must test
What is imatinib?
Inhibits multiple tyrosine kinases In: BCR-ABL fusion gene in CML and some ALL; CKIT in GI stromal tumours
What is sorafenib?
Inhibits RAF, VEGFR in hepatocellular carcinoma and renal cell carcinoma
