Precision Medicine Flashcards
1
Q
What is pharmacogenetics
A
- Application of genetic analysis to predict drug response, efficacy & toxicity
2
Q
Give 2 scenarios that involves use of pharmacogenetics
A
- DRUG DELIVERY & DEVELOPMENT: identifiying potential responsers and non-responders to drugs at early stages, using genetic variants that are markers of drug efficacy
- PRESCRIBING: genetic testing could be efficient in determining the best choice of a drug for a given patient & condition based on their individual genotype
3
Q
Is genetic testing affordable
A
Yes, due to the drop of the cost of genetic screening
2001: cost to sequence one human genome ~1M USD
Also widely available
4
Q
What is the 100,000 Genomes Project
A
- Screening of 100,000 genomes from 80,000+ patients affected by rare diseases or cancer
- Aim: understand role of genes in health and diseases
- Provides us with a lot of info and helps with the concept of personalised medicine
5
Q
Importance of pharmacogenetics and personalised meidcine
A
- 38% patients with depression do not respond to the first drug they are prescribed
- 40% patients with asthma do not respond to the most commonly prescribed drugs
- 43% for T2D, 50% for arthtiris and 70% for AD
- Each cancer is different in each individual
- Pharmacogenetics can provide insight into the role of genetics in diseases, such as different expression levels, and help with the concept of personalised medicines
6
Q
How does pharmacogenetics help with the concept of personalised medicine?
A
- Pharmacogenetics uses patient specific genetic info to predict their response to particular drugs
- This allows individualisation of healthcare
- It uses genetic and biomarker information to predict an individual’s risk of disease or to select the most effective and safest treatment
7
Q
What is personalised medicine
A
Using knowledge of enviornemnt, lifestyle and genetic factors to provide tailor-made prevention, diagnostic and treatment strategies for a defined group of individuals
8
Q
What is precision medicine
A
- Providing targeted therapies to individuals, primarily based on their molecular DIAGNOSTICS
9
Q
What is stratified medicine
A
- Grouping people based on their risk of disease or response to therapy using diagnostic techniques
10
Q
Traditional medicine therapy
A
- Prescribing the same drug at similar dose to all patients
- Some patients will have benefit but large proprotions will have no benefit or develop adverse effects
11
Q
Cancer vaccines are which type of medicine?
A
- Personalised
12
Q
Trastazumab & imatinib are which types of medicine?
A
- Stratified
13
Q
NSAIDs, SSRI, PPI, vaccines are which types of medicine?
A
- Empirical
14
Q
What are gene mutations?
A
- Changes to the DNA sequence
- Can happen at any time during the lifetime of a cell
15
Q
What are mutations caused by
A
- Viruses
- Cigarette smoke
- Alcohol
- Radiation
- Chemicals
- UV
16
Q
Somatic mutations
A
- Occur in non germline tissues (e.g. breast) so cannot be inherited
17
Q
Germline mutations
A
- Mutations in reproductive cells of an organism e.g. egg or sperm
- Can be passed on to offspring
- Cause cancer family syndrome
18
Q
How do mutations relate to oncology?
A
- Mutations in genes linked to cell survival and cell proliferation play a central role in oncogenesis and provide key links between mutagens and cancer
- Identifying these DNA changes can be crucial for diagnosis and in choice of treatment
19
Q
Two key aspects in mutations that relate to cancer - germline & somatic
A
- GERMLINE RISK: variants present in an individual’s genome since conception that increases risk of developing cancer
- SOMATIC MUTATIONS FOUND IN TUMOURS: mutations that occur during a patient’s lifetime that directly leads to oncogenesis
- You can already have predisposition of development of cancer if you carry certain mutations
- If your somatic cells end up with further mutations, risk becomes even higher
- Series of somatic mutations occuring in normal cells can also lead to cancer
- Both scenarios have consequences for treatment
20
Q
DNA sequencing - Sanger’s old technique
A
- Long chromosomes broken into short fragments
- Short fragments are templates
- ssDNA to be sequenced is primed with a short complementary primer
- Reaction divided into 4 batches
- Each reaction contains a different halting nucleotide: A, G, C, T
- Each replication continues until halting nucleotide incorporation
- Gel electrophoresis
This results in different sized in DNA fragment
This was the basic process in 1972, however has massively advanced now and is much quicker
21
Q
How many DNA sequences can be balanced now comapred to in Sanger’s method
A
- Now: 2 trillion DNA bases per slide
- Sanger: 10k DNA bases per gel
22
Q
How do we know that certain mutations relate to the hallmarks of cancer?
A
- From results from 100,000 Genomes Project and additioanl data from sequencing in isolated patients suffering from cancer
- This has allowed us to look into gene-expression pathway analysis etc and see how mutations relate to the hallmarks of cancer
23
Q
What is an oncogene
A
- A gene which has the potential to cause cancer when mutated
24
Q
What is a proto-oncogene
A
- Gene involved in normal cell growth and proliferation
- Thus if mutated can contibute to cancer
25
H-Ras Oncogene
* Many tumours activate this - very common!
* Normal cells: growth factors need to bind to receptors to allow a cell to grow, this binding leads to activation of certain phosphorylation cascades which in turn activate an intermediate protein: Ras
* Normal cells: Ras only active of GF bind to R!
* Ras will then signal down further and activate downstream TFs, stimulating the cell cycle etc
* In many cancers, Ras acquires mutations that makes it CONSTITUTIVELY ACTIVE - can signal downstream w/o presence of GF binding to R's = uncontrolled cell growth & division
26
Which hallmark of cancer is the Ras oncogene associated with?
1. Self-sufficient in growth factors
Mutated Ras is constitively active; does not require presence of GF binding to R's for it to be active
27
Loss of retinoblastoma suppressor
* If this is lost, it leads to an uncontrolled cell cycle
* Retinoblastoma inhibits formation of certain proteins required for the cell to progress in the cell cycle
* If lost = less control = increased liklihood of uncontrolled cell division
28
Which hallmark is associated with loss of retinoblastoma suppressor?
2. insenstivity to anti growth signals
Retinoblastoma tumour supressor regulates the cell cycle by inhibiting the formation of some prtoeins needed for the cell to progress - i.e. prevents the growth
Therefore, if it is lost, the cancer has insensivity to anti growth signals
29
Cancer cells producing IGF survival factors
* Insulin GF1 is the most important survival factor in the cell
* If IGF-1 binds to its receptor, this activates downsteam signalling cascades (including Ras) and allows the cells to proliferate and survive
* IFG1 is known to promote cancer by stimulating proliferation and preventing apoptosis
30
Which hallmark is associated with cancer cells producing IGF survival factors
3. evading apoptosis
Cancer cells produce IGF survival factors which bind to their receptor to activate downstream signalling cascades (including Ras) to allow cells to prolifeate and survive
The PI3K --> AKT --> mTOR pathway is key for evading apoptosis
Ras pathway key for proliferation
31
Cancer cells turning on telomerase
* Telomerase = enzyme that adds telomeric DNA sequences to telomeres
* Normal health cells: telomeres get shorter and shorter with each cell division; at the critical stage apoptosis is activated and cell is eliminated from system
* Cancer cells: activating telomerase = telomeres do not shorten allowing cancer cells to become effectively immortal
32
What hallmark is associated with cancer cells turning on telomerase
4. limitless replicative potential
Tolermase activity allows the cancer cell to have unlimited replication
33
Cancer cells producing VEGF inducer
* Vascular endothelial growth factor signalling modulates angiogenesis - stimulates new blood vessel formation from existing blood vessels to supply the tumour
34
What hallmark of cancer is associated with cancer cells producing vascular endothelial growth factor
5. sustained angiogenesis
VEGF stimulates formation of new blood vessels
35
Cancer cells inactivating E-cadherin
* E-cadherin is an inhibitory protein present in ECM tissue
* If lost, cancer cells increase mobility and can form metastases
* Thought to allow malignant tumour cells to dissociate from primary tumour & invade the ECM and surrounding stroma
36
Which hallmark of cancer is associated with cancer cells inactivating E-cadherin
6. tissue invasion & metastasis
* E-hadrin is an inhibitory protein present in ECM tissue
* If E-cadherin is lost, cancer cells can increase mobility and form metastasis, invading to other tissues
37
4 new hallmarks of cancer
* EMERGING HALLMARKS:
Deregulating cellular energetics
Avoiding immune destruction
* ENABLING CHARACTERISTICS
Genome instability and mutation
Tumour-promoting inflammation
38
Discuss the new hallmark of cancer: tumour promoting inflammation
* Ongoing chronic inflammation significantly increases risk of developing cancer
* Inflammation often mediated by TNF-A which in turn activates the TF NF-kB
* TNF-A = pro inflammatory cytokines
* TF NFkb mediates inflammatory processes, is key in the proliferation; survival; metastasis and angiogenesis of cancer cells
* All hallmarks so far are affected by NF-kB
* In many tumour cells, we will find a mutation in NF-kB that turns it constitutively active, thus contributing to survival of cancer cells
39
Knudson hypothesis
* Cancer is the result of ACCUMULATED mutations to a cell's DNA
* Sequence of events is not important
* Can have very different mutations in the same type of cancers - vary from patient to patient
* This is why we need individualised, personalised treatments for cancer
40
Genome instability and cancer
* In many cancer cells, there is also a persistent and increased genome instability which leads to mutations
