Protective, normal process to repair damage to DNA, Strand breaks and point mutations can be repaired efficiently if detected in damaged cells before mitosis
25% heritable mutations in DNA repair machinery genes e.g. BRCA1, TP53, Mismatch Repair (MMR) defects lead to development of colon, stomach, uterine cancers (syndromes), These DNA repair machinery genes are also dysfunctional in sporadic cancers
Highly mitotic cells are more likely to develop cancers, Can lead to aneuploidy, Copy number changes (loss/deletion) are seen in genes that normally pause the process of cell cycle and mitosis e.g. RB1 and TP53
Changes to gene expression through regulation by promoter or histone modifications - methylation and acetylation of DNA bases or histones, Can be inherited from a cell to its daughters - permanent effect
Clones - A population of daughter cells descended from a single progenitor cell, Genetically related - but new mutations can be gained, or lost, from a cell leading to tumour lesions being genetically and phenotypically heterogenous, Most cancers are descended from a single precursor cell hence they're monoclonal
1. Spatial intratumour heterogeneity (not every tumour cell in a lesion is exactly the same, genetically and phenotypically)
2. Cancer cells evolve through collection of gene variants and changes to their gene expression in order to adapt to and survive their environment (stress/treatment)
3. Evolution also allows cells to successfully metastasise and seed new sites in the body
If you take multiple small biopsies of the SAME tumour mass and analyse the genetic and epigenetic information you will detect spatial intratumour heterogeneity - not every tumour cell in a lesion is exactly the same, genetically and phenotypically
Cancer cells evolve through collection of gene variants and changes to their gene expression in order to adapt to and survive their environment (stress/treatment)
Evolution also allows cells to successfully metastasise and seed new sites in the body
W. WHEWELL: 'Bat with regard to the material weed, we can at least go so far as this-we can perceive that events are levoght about not by Insolated interpositions of Divine power, exerted in each particular case, but by the establishment of general laws.'
BACON: 'Yo eccelol, therefore, let no man cot of a weak econft of schelety, or an ill-applied sooderation, thlak or malatalo, that a aan can search too far or be too well stodiod in the book of Gol's weed, er is the look of Gor's works; divinity or philosophy; bot ther let son codeavoar an colles geogress ce peubelence in both.'
The continued existence of organisms which are best adapted to their environment, with the extinction of others, as a concept in the Darwinian theory of evolution
Have tight junctions and correct regulation of cell cycle and apoptosis checkpoints, requirement for growth factors to promote proliferation, adherence to basement membrane
1. Mutation in one cell confers freedom from normal growth control mechanisms
2. It proliferates without restraint, and does not die
3. During proliferation, new mutations can occur, some of which confer a growth, survival and invasion advantage - degrading the basement membrane
4. Further mutations occur. Although cells are related to a single progenitor (i.e. they are clonal), the tumour cells are mixed for phenotype and genotype. Each new population has a survival advantage for the environment it encounters
Trunk - shared, originating mutations present in every cancer cell - often called Founder, Clonal or driver mutations in oncogenes or tumour suppressors (key 'cancer genes')
Branches - early subclonal but common mutations
Twigs/leaves - recent, 'private' mutations present in a small subpopulation of cells
Selective - In response to external environmental pressures or therapy induced selection. Allows survival of cells that have a proliferative/survival or resistance advantage.
Neutral - Gene Variants, often called passenger mutations, that are non-beneficial to the cell but maintained in genome. This is called Random Drift.