lecture 32 Flashcards
Objectives?
- relate the role of important factors in normal vs cancer settings
- appreciate the various signals contributing to carciogenesis
- understand the role of oncogenes and tumour suppressor genes (TSGs) at the cellular lvel
- understand the basic genetics/heritability of major oncogenes or TSGs
- relate the various signalling pathways and genes in the context of complex networks
- know some of the major events that can trigger carcinogenesis
- learn some basic terminology specific to cancer causing genes
How have 5-year relative survival, incidence and mortality changed?
- 5 year: increasing
- incidence: increasing
- mortality: decreasing
What pathways are almost always altered in cancer?
- signalling pathways controlling cell survival, growth and differentiation and even metastatic potential are almost invariably altered in cancer
- it is components of these tumour ‘specific’ (a better term is ‘enriched’) signalling pathways which differ from ‘normal’ which need to be therapeutically targeted
What do we mean by signalling?
- transmission of information from one cell to another
or - transmission of information from the ‘environment’ to a cell
- biological communication at the level of subcellular/molecular
What was the view of the hallmarks of cancer in 2000?
- self-sufficiency in growth signals
- insensitivity to antigrowth signals
- tissue invasion and metastasis
- limitless potential for replication
- sustained angiogenesis
- evading apoptosis
What further mechanisms have been added?
emerging hallmarks
- deregulating cellular energetics
- avoiding immune destruction
enabling characteristics
- tumour-promoting inflammation
- genome instability and mutation
What are the molecular pathways in cancer?
- pathway circuitry dictates biological outcome and therapeutic response –especially important to understand this is cancer
- signalling pathways are very complex
- but can be divided into particular ‘circuits’
→ cytostasis and differentiation circuits
→ motility circuits
→ proliferation circuits
→ viability circuits - having drugs that target different circuits allows for more effective therapy
What are the major molecular events in cancer evolution?
environmental agents that damage DNA - chemicals - radiation - virsuses ↓ normal cell ↔ DNA damage ↓ failed repair (← inherited mutations in genes affecting: DNA repair, cell growth, apoptosis [only about 15%]) mutations in somatic cells ↙↓↘ 1. activation of growth promoting oncogenes 2. impaired apoptosis 3. inactivation of tumour suppressor genes ↘↓↙ altered gene products (proteins); abnormal structural and regulatory proteins ↓ malignant tumour
What are general cellular features typically seen in cancer?
- evolve slowly
- normal tissue has a very ordered structure of the different types of cells over different layers
- organisation in terms of each cell
- lose the organisation of the cells → dysplasia
- dysplasia also appears in benign tumours
- disorgisation/disordered signalling within cells becomes so problematic that the cells can break away, survive away from that tissue, metastasise to a different site
What genes are typically involved in cancer?
- four classes of normal regulatory genes are the prinicipal targets of genetic damage relevant in carcinogenesis:
- genes involved in DNA repair
- growth-promoting proto-oncogenes
- growth-inhibiting tumour suppressor genes
- genes that regulate programmed cell death (i.e. apoptosis)
→ remember that in almost all cases of carcinogenesis, all classes of genes are involved and the pathways of which they are part cooperate/interact
What are types of mutations in cancer?
- errors in DNA replication not repaired – DNA genes e.g. BRCA1 and BRCA2, leads to accumulation of erros – some genomic regions are more prone to this: mutations hotspots in oncogenes, tumour suppressor genes (TSGs), regulatory regions (of oncogenes, TSGs), controlling levels of expression
- point mutations – activating in oncogenes; inactivating in TSGs
- amplification of oncogenes (multiple copies)
- chromosomal rearrangements
What is the role of DNA repair genes in cancer?
- aberrant function of this gene class may be an early evenet or the event that allows the rapid accumulation of secondary etc mutations
- affecting genes encoding oncogenes and TSGs
e.g.
BRCA1 and BRCA2 and homologous recombination proteins involved in repairing double-strand breaks
mutations in these genes → breast, ovarian and pancreatic cnacer
treated with PARP inhibitors, platinum salts
MSH2 and MLH1 are mismatch repair proteins that repair things such as base mismatches, insertions and deletions
→ colorectal
What are types of DNA damage?
- single strand break
- double strand break
- bulky abducts
- base mismatches, insertions and deletions
- base alkylation
What is a mutation?
- a mutation is any change in a DNA sequence away from normal
- this implies there is a normal allele that is prevelent in the population and that the mutation changes this to a rare abormal variant
- wild-type proto-oncogene → mutated oncogene (e.g. via point mutation) → constitutively active protein
What are oncogene amplifications?
- e.g. N-MYC
- multiple copies
- break off of N-MYC genes forming mini-chromosomes called doube minutes
What are gene translocations and fusions?
- e.e. BCR-ABL
- geneation of oncogenic chimaeric molecules
- chronic myelogenous leukaemia
- ABL (chr 9 → chr 22)
→ tyrosine kinase
What are classic immunohistochemical markers for cancer?
- proliferation markers
- PCNA (proliferating cell nuclear antigen)
- Ki-67 (aka MIB-1) → the name reflects the city of origin (Kiel, Germany) and the number of the clone recognising a specific antigen in Hodgkin lymphoma
