4: Darwinian Evolution Of Cancer Flashcards
What is a selective advantage?
A cell that has mutations that may allow a cell to overcome growth constraints or out-compete other cells
(‘Fitness’)
What is positive selection?
If a mutation confers a selective advantage
Allows cell to undergo clonal expansion
What is negative selection
If a mutation confers a selective disadvantage (cell extinction)
What does it mean when a mutation is selectively neutral?
It has no selective advantage or disadvantage
What is a driver mutation
Mutations which are essential for the development of cancer
(Mutations which confer a selective advantage)
What are passenger mutations?
Mutations which are present in cancers but which are selectively neutral
What is linear evolution?
Successive “clonal sweeps” driven by selection.
What is branched evolution?
Multiple clones and sub-clones evolving simultaneously if there is equal selective advantage in mutations.
Growth constraints are avoided, no mutation has a select advantage
What is neutral evolution?
No selection of mutations, resulting in multiple clones
What is punctuated evolution?
A large number of mutations in a short burst. Multiple clones are present, there is often an advantage for one mutation over the others.
What is convergent evolution?
Where a feature is acquired by different clones.
Different background > same end point
What is divergent evolution?
Acquisition of new features from a common ancestor
What are truncal mutations?
Mutations that occur early in the development of cancers, and are seen in dominant clones.
Aka public mutations
What are branch mutations?
Mutations that occur later on in cancer development, after truncal mutations. They are often seen in the sub-clones
Aka private mutations
Briefly describe the Darwinian evolution of cancer
- Tumours arise from normal tissue, any tissue type can > cancer
- Normal tissue converted > tumour by acquisition f driver gene mutations
- Evolution of cancer from normal tissue may take decades
- Normal tissues > cancer via intermediate precursor lesions
Why may it take decades for normal tissue to develop into cancerous tissue?
DNA mechanisms keep mutations suppressed efficiently.
Acquiring and selecting for the mutations may take a long time, especially if they are somatic, not germline.
Briefly outline the adenoma-carcinoma sequence, and mutations involved.
Normal tissue > Uni-criptal adenoma
- APC mutation. One crypt is abnormal.
> Poly-crystal adenoma
- KRAs mutation. Invasion of multiple crypts.
> Colon carcinoma
- 18q mutation.
> metastatic malignancy
- TP533 mutation
Which sequence describes the histological evolution of colorectal cancers?
Adenoma-carcinoma sequence
What model describes the genetic basis of tumour evolution?
Fearon-Vogelstein
T or F: Precursor legions are always histologically present?
False: Precursor lesions may not always be histologically apparent, sometimes they are not visible through microscope
T of F: Histological evolution is specific to adenomacarcinomas?
False: almost every other organ system shows similar histological evolution of cancer
Describe the outline of a general evolution of histology for most cancers?
- Normal tissue
(- Metaplasia) - Low grade/ mild dysplasia
- Moderate dysplasia
- High grade/ severe dysplasia
- Carcinoma
(- Invasive malignancy)
What does tumour evolution allow cells to do?
- Overcome growth constraints
- Outcompete other cells
What imbalance is tumour development caused by?
Rate of cell division and rate of apoptosis
List a few gradients (of cellular processes/components, not specific proteins) described in the structure of colonic mucosa
- Morphogens
- Matrix component
- Signalling activity
- Cell division/apoptosis
Which signalling factors increase as you go from the base of the crypt to the top in the colonic mucosa?
- APC
- BMP2/4
- EphrinB
Any signalling factors that regulate differentiation/apoptosis
Which signalling factors decrease as you go from the base of the crypto to the top in colonic mucosa?
- Wnt
- EphB1
(Signalling pathways that increase proliferation)
How many mutations are required for malignant conversion of a normal cell?
Around 4-5
Generally, at what stages do APC and TP53 mutations occur in tumour evolution?
APC early
TP53 late
How come mutations generally occur at the same time during tumour evolution despite mutations being random?
Mutations are selected for when they give maximal growth advantage
Which clones may be selected for/against when chemotherapy is given?
- Resistant mutation clones may be selected for
- Sensitivity mutations may be selected against
What is an example of a resistant mutation following anti-EGFR therapy?
KRAS mutations
What is an example of a sensitivity mutation selected against following PARP inhibitor therapy?
BRCA1
What type of evolution is in colorectal adenomas?
Branched
Describe tumour heterogeneity in colorectal cancers
in terms of tumour evolution
- Groups of mutations present in all tumour regions
- May result in a clonal sweep (linear evolution)
- Dominant clone undergoes further branching evolution
-Results in sub-clone with private mutations in different regions of the tumour
What is chromothripsis
a mutational process
large stretches of a chromosome undergo massive rearrangements in a single, catastrophic event.
chromosome region fragments into smaller pieces, re-joins, and rearranges, leading to a new genome configuration
When may punctuated evolution occur
When there are events such as chromothripsis
Fragmentation of chromosomes with random stitching together
Leads to multiple clones which compete, dominant clones may emerge
T or F:
- Most tissues have a specific architecture
- Tissues undergo constant turnover/renewal
- A small number of stem cells are theoectically responsible for generation of a new tissue
- Cells within tissue may change as part of renewal process
- True
- True
- True
- True, cells mature as they develop.
How may the tissue of origin of a liver cancer from a skin cancer be identified?
- Cancers reflect the tissue of origin.
- Squamous cells produce keratin, and so do squamous cell carcinomas
- It still produces the keratin after metastasizing.
- Biopsy of liver carcinoma may reveal keratin, showing cancer of origin
Can metaplasia result in the evelopment of dysplasia in precursor lesions?
Is this usually the case?
Metaplasia is the change from one state to another, arising due to change in environment.
This change may result in instability, and increased risk of dysplasia.
Metaplasia does not always result in dysplasia, and dysplasia is not always the result of metaplasia.
T or F:
- Precursor lesions will always progress to invasive malignancy
- Precursor lesions are always morphologically distinct
- Metaplasia increases risk of malignancy
- If precursor lesions can be identified, then screening programs can be developed
- False
- False
- True
- True
Which evolution if characterised by consecutive clonal sweeps?
Linear evolution
is it true that the evolutionary models are mutually exclusive?
No, the evolutionary models may operate simultaneously during tumor progression as two independent molecular clocks.
What kind of advantage do passenger mutations classically confer?
Neutral/ no advantage
Which evolution is most likely to result in clonal expansion?
Branched evolution
T or F:
TP53 mutations are never selected early in colorectal tumours?
False
The general model suggests that TP53 mutations are normally selected for late. However, the biology of cancers occurring sporadically may have early mutations of TP53 gene
Explain how Barrett’s metaplasia is a healing response
- prolonged tissue injury in the esophagus due to gastroesophageal reflux damages the squamous epithelium in the oesophagus
- metaplasia occurs in response, changing the squamous to columnar epithelium.
- despite the increased risk of cancer due to Metaplasia, it is a healing response to the reflux.
T or F:
- Adenomas will always evolve into adenocarcinomas
- Adenomas may become sarcomatous
- KRAS mutations can be used to make a diagnosis of adenocarcinomas
- F: not all precursor lesions > carcinomas
- F
- F:adenocarcinomas are usually diagnosed mostly from histology of the cancer, but one mutation cannot diagnose a cancer alone.
Evolution of a cell to escape cetuximab (anti-EGFR therapy) my occur through which mutation?
KRAS. Mutated KRAS can still cause increased signalling despite upstream EGFR inhibition.
How many mutations are required for malignant conversion of a normal cell?
4 or 5 positively selected driver mutations
