Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Pharmacogenomics > Week 6 > Flashcards

Week 6 Flashcards

1
Q

What is cancer?

A

Group of related, complex disease.
Abnormal cell growth/ division (cell proliferation
- Spread to other regions of the body (metastasis)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Genes and cancer

A

Cancer is, in essence, a genetic disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the hallmarks of cancer?

A
  1. Evading growth suppressors
  2. Avoiding immune destruction
  3. Enabling replicative immortality
  4. Tumour promoting factor
  5. Activating invasion & metastasis
  6. Inducing angiogenesis
  7. Genome instability & mutation
  8. Resisting cell death
  9. Deregulating celular energetics
  10. Sustaining proliferative signalling
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What percentage of cancer is caused by sporadic mutations?

A 
80-90% 
Somatic mutations 
1. Spontaneous 
2. Induced 
Could be from environmental agents or just be form the replication
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What percentage of cancer is caused by hereditary mutations?

A

5-10%

Germ line mutations Single genes that cause these disorders.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

How do driver mutations work?

A 
Initiating mutation 
Acquisition of genomic instability 
Acquisition of cancer hallmarks 
Further genetic evolution 
- Genome is not replicated accurately, by chance you may get a change in a gene, this could by chance cause angiogenesis, due to the constant changes of the genome in the cells.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Why are studies leaning towards personalised cancer treatment?

A

Just because the cancers are the same types and that they have the same causes, does not mean they will respond to the same specific therapies,, However they could split of based on genetics.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is the pathogenesis of the BCR-ABL1 fusion gene?

A

95% = translocation
- ABL1 is a tyrosine kinase,
in normal cells, has role in cellular differentiation and regulation of the cell cycle.
- The BCR-ABL1 fusion gene causes a permanently active tyrosine kinase, causing uncontrolled proliferation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How does Imatnib work?

A

Blocks the ATP binding centre of Bar-Abl thus inhibiting its phosphorylation activity.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

How do BRAF inhibitors treat people with Melanoma?

A

BRAF mutations - treated with inhibitors
but only if they have the V600E mutation
(therefore they don’t inhibit the wild type BRAF)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is an example of a BRAF inhibitor?

A

Vemurafenib, is reversible, ATP-competitive inhibitor of the kinase domain of BRAF.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How many melanomas carry the mutation in BRAF?

A

40-60%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What do BRAF mutations cause?

A

activation of downstream signalling through the MAPK pathway.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

In 2011 what happened in regard to vemurafenib?

A

Drug trial showed:

  • 63% reduction in risk of death,
  • 74% reduction in disease progression
  • Compared to standard chemotherapy.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Why is vemurafinib not the cure for melanoma?

A

When you blocking part of the pathway, the cancer works out a way round the pathway, however due to its rapid response, it gives people a few more months.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is the cause of 80% colorectal tumours?

A

Over expression of EGFR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is the treatment for colorectal cancer?

A

Monoclonal antibodies - which block ligand-induced EGFR tyrosine kinase activation, blocking downstream signalling pathways which would normally cause proliferation, angiogenesis, migration and survival (cetuximab or panitumumab)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

If there is a mutation in NRAS/KRAS why can’t anti-EGFR antibodies work as a therapy?

A

Because blocking the EGFR would usually stop the pathway, but if there is a mutation where KRAS/NRAS is always active, the pathway would be active all the time.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

If they sequenced the KRAS exon 2 and 3 and from a tumour sample this had a clear peak what would this mean?

A

There is a mutant, there is base which does not fit with the alignment of bases.

20
Q

What is the response with panitumunab to KRAS mutation?

A

0% because it blocks only the EGFR, but if there is a KRAS mutation then it would be active anyways.

21
Q

What is the response to panitumunab when they are KRAS WT?

A

Better survival increase compared to standard treatment.

22
Q

What happens when someone has a mutation in BRAF?

A

They have a poor prognosis regardless of therapy.

23
Q

When looking for an inherited disorder, which is heterozygous, what would it show through Sanger sequencing?

A

It would show two peaks, because one would be normal one would be mutant, so they would show up on top of each other.

24
Q

What are the problems with sequencing DNA from tumour samples?

A

There could be non-cancerous cells mixed in with cancerous.
Also the cancer cell, due to the rapid replication would not have all their DNA exactly the same.
This makes it hard for detecting the mutations.

25
Q

When might they think that the mutation is correct?

A

If the rest of the sequencing is really clean and you can see the mutation is the forward and reverse.

26
Q

What are the Ras proteins and what do they do?

A

KRas, HRas and NRas

Function as GDP-GTP regulated binary switches

27
Q

How does Ras switching work?

A

Alternation between GDP bound “off” state to GTP bound “on” state

28
Q

What controls whether Ras is on or off?

A

GDP to GTP is controlled by guanine nucleotide factors (GEFs) SOS1 and SOS2,
GTP to GDP controlled by GTPase-activating proteins (GAPs), which terminate the ‘on’ state by catalysing the hydrolysis of GTP to GDP

29
Q

When you have specific mutations in Ras what happens?

A

The protein is then resistant to the hydrolysis meaning it remains the GTP form and therefore remains chronically active.

30
Q

What are Gastrointestinal Stromal Tumour?(GIST)

A

Sarcoma - Tumour of the soft tissue
Rare tumours of the GI tract
Most common between 50-70 years
Surgery (small accessible tumours) Treatment

31
Q

What would the mutation be in for GIST?

A

The mutation would be in KIT or PDGFRA which are both receptors for tyrosine kinase. causing the receptors to be active all the time

32
Q

What treats GIST?

A

Imatnib (Tyrosine kinase inhibitor) binds to the ATP binding sites of KIT, PDGFRA

33
Q

What is the name of the multi-target tyrosine kinase inhibitor and what can it treat?

A

Sunitinib - And it would inhibit KIT and PDGFRA which are tyrosine kinase inhibitors

34
Q

What was the drug for Breast cancer, which would only work on some people?

A

Trastuzumab (Herceptin)

35
Q

How does (Herceptin) Trastuzuab work for people with breast cancer?

A

HER2-targetting monoclonal antibody which binds to the over expressed receptor and inhibits the pathway, which is only given to patients if the breast cancer is caused by the over expression of HER2, which would normally cause more proliferation and survival.

36
Q

How is breast cancer HER2 over-expression tested for?

A

IHC - Tests for the over expression

FISH - Testing for the amplification

37
Q

How would you do IHC to look for the over expression in breast cancer?

A

Immuno-Histo-Chemistry
you stain the tumour sample with an antibody that has been raised against HER2. If they don’t stain it would not be due to the over expression.

38
Q

How would you do FISH

A

Fluorescence-insitu- hybridisation
Which is looking at the gene which has a probe for the HER2 gene, see that there is normally two signals of green, however in someone with amplification, there is multiple signals of green.

39
Q

What percentage of lung cancer is Non Small Cell Lung Cancer?

A

80%

40
Q

What does the drug Gryfitnib target?

A

The ATP cleft within the tyrosine kinase domain of EGFR.

41
Q

Why do only certain patients respond to Getfitnib?

A

Due to the mutations in exon 18-21, because they lead to increased growth factor signalling and confer susceptibility to the inhibitor.

42
Q

Why could someone develop resistance to a drug like getfitnib?

A

They likely would have another mutation which is amplified after all the other cells die due to Getfitnib.

43
Q

What would be the protocol if someone develops a mutation and becomes resistant to Getfitnib?

A

They would get prescribed third generation tyrosine kinase inhibitors.

44
Q

What are ALK inhibitors and what is the criteria for the drug?

A

Treats Non Small Cell Lung Cancer but only those with ALK fusion variant, which are mostly comprised of EML4 gene with the ALK gene.

45
Q

What happens when there is an ALK fusion gene?

A

Intracellular tyrosine kinase domain of the ALK receptor is constitutively active. This leads to inhibition of apoptosis and promotion of cell proliferation

46
Q

What is the future for overcoming cancer?

A

Extending the scope e.g. looking at other V600 mutations in malignant melanomas and overcoming resistance e.g. second and third generation tyrosine kinase inhibitors.

47
Q

What is the 100,000 genome project -Cancer arm?

A
  • Sequence DNA from healthy and cancerous cells.
  • Compare two sequences
    Identifying genomic changes causing the cancer.
  • Improving diagnosis.
  • Helping clinicians to select the right treatments.
  • Develop new drugs.

Pharmacogenomics (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions