Cancer Evolution Flashcards
what features are shared by both natural selection and cancer?
- variation in the population
- traits ust be heritable
- affect survival/reproduction fitness
- clonal expansion
what are some possible reasons that humans have more cancer than other species?
- long post reproductive lifespan
- mis-matched to risk factors generated by civilisation
- highly invasive placentas produced by stem cells pre adapted to metastasis1
why is clincal cancer not even more common?
we are not great at detecting it and the cancer lottery (a combination of DNA damagin exposures, modulators of risk and chance all contribute to wether mutations lead to cancer)
what is the somatic mutation theory (SMT) of cancer?
cancer begins with a genetic change in a single cell that passes it on to its progeny thereby creating a clone of cells - cells within this population acquire further mutations so that eventually a sub-clone emerges that is able to grow or metastasize sufficiently to cause death of the host
- cancer is mediated by somatic evolution at the level of the cell
what is microevolution?
change in the genetic composition that occurs over time in a population
what is macroevolution?
major evolutionary change at or above the level of a species
what is the punctuated pattern of evolution
discontinuous acquisition of mutations over time with periods of relative stasis. mutations may be acquired in distinct patterns and be co-located, or can be distributed across the genome
(short periods of rapid evolution followed by longer periods of stasis in which no change occurs)
what is gradualism
a policy of gradual reform rather than sudden change or revolution
what is gradual evolution
an iterative pettern of mutation acquisition and selection over time
what is somatic evolution?
accumulation of (epi)mutations in somatic cells of your body during your lifetime
these occur in normal tissues and increased with age/ risk exposures
they may effect the fitness of those cells and lead to positive selection of mutant clones
what is neoplastic progression?
the somatic evolutionary process by which normal tissue changes to malignant (cancerous) tumour
what is a clone?
set of cells that all descend from a common ancestor cell -usually distinguished through heritances of distinctive genetic lesions that occured in the ancestor cell
what is a clone?
set of cells that all descend from a common ancestor cell -usually distinguished through heritances of distinctive genetic lesions that occured in the ancestor cell
Number of clones, measuring how different they are can directly correlate with individual risk of developing cancer in your l lifetime.
what are driver mutations?
mutations that give a selective advantage to a clone in its microenvironment, through either increasing its survival or reproduction. driver mutations tend to cause clonal expansion
what are passenger mutations?
mutations that have no effect on the fitness of the clon but may be associated with a clonal expansion because it occurs in the same genome with a driver mutations. this is know as a hitchhiker in evolutionary biology
what is chromoplexy?
disordered recombination of the chromosome in one cell division - causes genetic material from one or more chromosomes to become scrambled as multiple strands of DNA are broken and ligated to each other in a new configuration.
what is chromothripsis?
a mutational process by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes - a chromosome is shattered and abhorrantly stictched back together
what is the classic model of cancer evolution?
linear successive clonal expansion, driven by the accumulation of genomic lesions that are preferentially selected by the tumour environment
give four mechanisms of diversity
in the genetic makeup of tumour cells
- numerical chromosomal instability
- somatic mutagenesis
- structural chromosomal instability (eg chromoplexy, chromothripsis)
- epigenetic heterogeneity
rather than linear evolution, what type of evolution more accurately describes that seen in cancer?
branching evolution
what are the promises and challenges in translating insights into tumour evolution to help therapy
Promises;
* clonal therapy targeting clonal mutations to eradicate all tumor cells (targeted therapy, immunotherapy)
* preempt resistance
* adaptive therapy to chronically control disease
Challenges;
* sampling stretegy
* inevitable clonal monotherapy resistance
* bespoke combination therapies complicate toxicity and licensing
what are the promises and challenges in translating insights into tumour evolution to monitoring?
promises;
* bespoke monitoring based on tumor-specific mutations
challenges;
* high cost
* novel mutations of subclones may be missed
* early detection of relapse may not improve outcome
what are the promises and challenges in translating insights into tumour evolution in early diagnosis and stratification
promises;
* identify changes meriting intervention
challenges;
* normal tissues contain canonical cancer mutations
* early diagnosis may not improve outcome
what are the promises and challenges in translating insights into tumour evolution in prevention
promises;
* mutational signatures can suggest etiological factors that drive early tumorigenesis
challenges;
* exogenous factors may not be preventable
* some tumours may not be preventable (such as those of children and young adults)
