5.6 - Cancer Genetics Flashcards
1
Q
Pre-requisite concepts (molecular biology)
A
- the components of a cell need to function properly for a cell to behave normally
- splicing and modifications can result in many proteins from a single gene
- in every cell in your body, the genome is the same, but the proteins expressed by each cell is different
- diffusion and Brownian motion (random entropic motion) cause binding (rather than magnetism)–> conformational change when it binds
- cellular machinery is complex so errors will happen
2
Q
What is cancer?
A
- cancer is a condition where cells in a specific part of the body grow and reproduce uncontrollably
- the cancerous cells can invade and destroy surrounding healthy tissue, including organs
3
Q
What is tumour heterogeneity?
A
- describes the observation that different tumour cells can show distinct morphological and phenotypic profiles
- includes cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential
- this phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity)
4
Q
What are driver mutations?
A
- driver mutations are those that drive cancer initiation and progression
- cancer risk genes are those genes in which driver mutations can occur - around 736 genes in the human genome identified
5
Q
What are passenger mutations?
A
- passenger mutations are those that do not drive cancer initiation and progression
- mutations occur constantly, not just in cancer
6
Q
What are proto-oncogenes?
A
- type of normal gene that produces a protein that promotes cell growth and proliferation e.g. k-Ras
- driver mutations in a proto-oncogene could lead to cancer
- a proto-oncogene with driver mutations is called an oncogene
7
Q
How does mutation in k-Ras cause cancer?
A
- k-Ras is the gene which encodes Ras protein
- normal state - signalling results in k-Ras being switched on –> Ras protein –> cell proliferation
- after growth, something will come and switch it off again
- driver mutation in k-Ras = it cannot be switched off
8
Q
What is a tumour-suppressor gene?
A
- type of normal gene that produces a protein that helps limit cell growth and proliferation e.g. TP53
- driver mutations in a tumour suppressor gene can lead to cancer
- Knudson hypothesis (AKA two-hit hypothesis) is the hypothesis that most tumour suppressor genes require both alleles to be inactivated to cause a phenotypic change
9
Q
How does mutation in TP53 cause cancer?
A
- TP53 is the gene which encodes p53
- p53 protein limits cell growth and allows regulation - unwinds histones around DNA, pulls in an RNA polymerase and allows transcription
- p53 is expressed when there is DNA damage and cell growth needs to be arrested, and binds to part of the gene to limit cell growth –> removes histones, attracts RNA polymerase
10
Q
What do hallmarks of cancer mean?
A
- a set of functional capabilities acquired by human cells as they make their way from normalcy to cancer
- driver mutations in cancer risk genes can result in the acquisition of one or more of the hallmarks of cancer
11
Q
What are examples of hallmarks of cancer?
A
- sustaining proliferative signalling - e.g. k-Ras
- evading growth suppressors - e.g. p53 mutation
- nonmutational epigenetic reprogramming - e.g. epigenetic tags on cell growth/arrest genes that can be switched on/off
- avoiding immune destruction - immune cells can sometimes kill cancer cells, which can acquire capability to avoid this
- enabling replicative immortality - dividing cell has telomere which reduces in size until cell killed; cancer cells can evade this mechanism
- tumour promoting inflammation - tumour can hijack immune system to release substances which promote its growth
- polymorphic microbiomes - cancer cells cause microbiome to release growth factors
- activating invasion and metastasis - allows tumour to spread
- inducing or accessing vasculature - cancer cells need close access to blood vessels so they can induce angiogenesis
- senescent cells - cancer cells can cause cells to come out of senescent state and grow
- genome instability and mutation - e.g. BCR-ABL - chunk of chromosome 9 binds to chromosome 22 –> BCR-ABL fusion protein –> chronic myeloid leukaemia
- resisting cell death
- deregulating cellular metabolism - cancer cells cause massive glucose uptake –> lactate = energy (Warburg hypothesis)
- unlocking phenotypic plasticity - in certain conditions
12
Q
What is a germline mutation?
A
- a mutation in the reproductive cells (egg or sperm)
- passed on from parents to offspring
- present in entire genome
13
Q
What is a somatic mutation?
A
- mutation in any cell of the body except the germ cells (egg or sperm)
- not passed on from parents to offspring
14
Q
What is the Cancer Gene Census (CGG)?
A
- ongoing effort to catalogue those genes which contain mutations that have been causally implicated in cancer (cancer risk genes)
- there are 736 cancer genes in the most recent version
- each of these genes have the potential to have driver mutations, resulting in the acquisition of one or more of the hallmarks of cancer
15
Q
What are cancer risk genes?
A
- genes which contain mutations that have been causally implicated in cancer
- we all carry certain genes that are normally protective against cancer
- these genes correct any DNA damage that naturally happens when cells divide
- inheriting faulty versions/variants of these genes significantly raises your risk of developing cancer, as the altered genes cannot repair the damaged cells, which can build up and form a tumour
