Cancer Genes Clonality Flashcards
Somatic alterations accumulate even before cancer starts
What is an example?
Deep sequencing of normal oesophagus from healthy and cancer donors revealed that mutations in Notch 1 and TP53 were mutated more frequently in non cancer compared to cancerous samples
How is phylogenetics used to represent cancer evolution?
A phylogenetic tree is a representation of the evolution of a system
The trunk = compendium of mutations shared by all cancer cells within the clone
The root of the tree = the most recent common ancestor of all cancer cells
All mutations that occur after the most recent common ancestor are subclonal
What are two evolutional models of cancer?
- Linear (multistep) evolution
2. Punctuated (crisis-driven) evolution
Why is cancer an evolutionary system?
Basic principle of Darwinian evolutionary systems apply to cancer
Reproductive individuals = cancer cells
Common descent = cell(s) of origin
Natural selection of the driver variants
Negative selection of the damaging variants
(Quasi)neutral effect of passenger variants
What are the differences between evolutionary biology and cancer biology?
- Timescale: Evolution of cancer occupies lifespan of an individual, while instead evolution of species is a much larger time scale
- Reproductive system: In many species there is sexual reproduction, where as in the cancer cell the reproductive system is the cell that divides into daughter cell
- Environment: In case of evolution of species environment is external environment, in cancer environment is within organism e.g non cancer cells that surround cancer cells
- Concept of damaging: Damaging in context or species evolution concerns death of species and the child within said species with a damaging mutation will not survive. In the case of evolutionary biology refer to damaging mutations as those that alter function of gene and thus can be beneficial for tumour as they either lead to higher expression of gene or gain or function or cause a loss of function for gene which in the case of tumour suppressors is enhancing activity of tumour and favouring evolution of tumour
- Role of epigenetic: Epigenetic’s can drive modification in cancer
- Differences in selection pressure. In evolutionary biology genome is relatively stable- negative selection , cancer genome is highly variable and are under weak positive selection, and this is true for evolution of normal tissues
How is cancer clonal evolution driven by somatic alterations?
During gestation there is an acquisition of mutation which is an intrinsic property of all cells. When cells, particularly the stem cell lineage divides since duplication of the DNA is not a perfect mechanism mutations appear. Mutation rate is very low in somatic cells thus system is well controlled.
Throughout life there may be exposures to environmental risk of carcinogenesis, and thus increases accumulation of mutation and can occur during early clonal expansion.
Mutator phenotype (increase in mutation rate of cancer cells) may occur once benign tumour forms
Tracing mutations before cancer begins is important
What is the big bang model of tumour evolution?
- Individual subclones with distinct mutational patterns coexist within the tumour and will grow at similar rates (no selection)
- Cancer evolution is dominated by neutral evolutionary dynamics
What are the three consequences of tumour evolution?
- Inter-tumour heterogeneity
- Intra-tumour heterogeneity
- Subclones within cancer clones, not all cells harbour same mutation
- Mutation frequency is proportional to the fraction of mutated cells
3. Mutational signatures
What are two different forms of mutations in cancer?
Driver mutations = mutations that confer a selective growth advantage to the tumor
Passenger mutations = mutations that have no effect on the neoplastic process
Do all mutations contribute to cancer? Give an example
No
Passenger mutations
What three selection forces act upon genome?
Negative force is strong and selects against a given mutation because this mutation is damaging for the genome.
Positive selection: Mutations are positive for cancer cells
Neutral: Some mutations that do not confer any advantage
Mutations under positive selection are drivers of the cancer and therefore…
Tend to reoccur in different cancers in different patients because when they randomly occur they are selected for
What did one study investigating selection forces in cancer find?
Knowledge of cancer driver depends upon whether cancer is heavily studied and of sample size is large enough to identify recurrent genes
Cancer drivers are not cancer specific
True or false
False
they are cancer specific
Why is knowledge about cancer drivers, their clonality and models of cancer evolution important?
(1) Prediction of tumour relapses
Study found two patterns of clinical evolution
Pattern 1: The same dominant clone in the primary tumour evolved into the relapse clone, patients inadequately treated or with driver mutations in the founding clones resistant to therapy
Pattern 2: A minor subclone survives, gains mutations, and expands at relapse. Specific mutations contribute to chemotherapy resistance
(2) Personalised cancer treatment
Study found that Synchronous colorectal cancer tumours were mostly biclonal or polycolonal. This impacts cancer therapy - one of the personalised cancer treatments for SCRCs are anti EGFR antibodies which block one of the oncogenic pathways that is most active in colorectal cancer. Found different mutations in the downstream of the EGF pathways in the two tumours meaning if patients were treated with anti-EGFR antibodies, one lesion may be sensitive and the other resistant and therefore a personalised is needed for every cancer the patient may have.
- Select neoantigen immunotherapy
based
- Exploiting modified proteins as new antigens for T-cell activation
- When neoantigens are subclonal they are represented in a fraction of cells, they are not sensitive to immunetherapy. However when high in numbers and clonal, tumours are more sensitive to immunotherapy and more cancer cells will be destroyed. This is because for new cancer cell to be recognised by t cell new antigen needed, if the new antigen is present in all cancer cells, all these cancer cells will be killed. Thus knowing clonality of mutations is important to understand response to therapy.
