Brainscape's Knowledge GenomeTM

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


See full index

FRCPath Genomics > 05 - Cancer > Flashcards

05 - Cancer Flashcards

1
Q

Name 3x Tumour Suppressor Genes and describe the cancer associated with them

A

1 - RB1

  • controls cell cycle arrest. When phosphorylated, Rb1 binds to E2F, inhibiting the role of E2F as a transcription factor
  • loss of RB1 = Retinoblastoma

2 - p53

  • at the centre of signalling network of cell cycle control
  • p53 is activated upon cellular stress. It becomes phosphorylated which means it can escape repression by MDM2. Acts as a TF = cell cycle arrest
  • Familial mutations ass. with Li-Fraumeni Syndrome

3 - CDKN2A

  • encodes 2 genes:
  • P16 INKA - which inhibits CDK4/6, which keeps Rb1 phosphorylated and thus = cell cycle arrest
  • P14 ARF - which destabilises MDM off p53 = cell cycle arrest
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the 5 types of oncogenes

A 
1 - Secreted Growth Factors
2 - Growth Factor Receptors
3 - Signal Transducers
4 - Inhibitors of apoptosis
5 - Transcription Factors
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Provide an example of a Secreted Growth Factor Oncogene

A

> SIS gene

> encodes protein similar to PDGF = activates cell proliferation

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

Provide an example of a Growth Factor Receptors Oncogene

A

> EGFR

> NSCLC

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

Provide an example of a Signal Transducers Oncogene

A

> PI3Ks - family of protein kinases
phosphorylate Inositol containing lipids:
PIP + P = PIP2 + P = PIP3
PI3k pathway deregulated in most cancers
GoF mutations

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

Provide an example of a Oncogene which inhibitors apoptosis

A

> BCL2 gene
overexpression of BCL2 gene associated with Follicular lymphoma
t(14;18) BCL2/IgG locus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Provide an example of a Transcription Factor Oncogene

A

> EWS/FLI1 fusion in Ewing Sarcoma acts as a TF

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

What domain are mutations found in EGFR in NSCLC?

A

Tyrosine Kinase domain - encoded by exons 18, 19 and 21

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

what is the common drug resistant mutation in EGFR

A

Thr790Met

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

What type of receptors to PI3Ks transduce signals from

A

RTKs - receptor tyrosine kinases

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

What type of receptors does the RAS signalling pathway transduce signals from

A

G-protein coupled receptors

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

Describe 4 mechanisms/mutations which occur in oncogenes to drive malignancy

A

1) GoF point mutations
- BRAF V600E results in signalling pathway constitutively active = malignant melanoma

2) Amplification
- HER2 - human epidermal growth factor receptor 2
- expressed on breast cell surface but increased copy no. on breast cancer cells = cell hypersensitive to growth factors

3) Translocations creating novel Gene fusion
- BCR-ABL1 = tyrosine kinase activity (constitutively active)

4) Translocation of oncogene into a transcriptionally active region (e.g. Ig locus).
- Burkitt Lymphoma, t(8;14) - MYC gene into Ig locus

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

What is the testing pathway of Lynch Syndrome referrals

A

> Tumour tissue is 1st sent for IHC testing - to look for levels of the MMR protein.

> If Loss of MMR protein detected and is MLH1 = MLH1 hypermethylation testing (15% sporadic cancers)

> if NO evidence of MMR protein loss = proceed with MSI studies

> no mutations - proceed with Germline mutation testing

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

Tumour Suppressor genes can be categorised as:

A

GATEKEEPERS

  • control cell cycle
  • RB1, p53, APC

CARETAKERS

  • maintain & protect integruity of genome
  • MLH1, MSH2, MSH6
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What types of mutations tend to be associated with TSG

A

Loss of function or Inactivation of TSG

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

Tell me about Retinoblastoma

A
  • Mutations in RB1 gene
  • aggressive childhood cancer or eye
  • can be unilateral (sporadic) or bilateral (using familial - often has a gremlin mutation)
  • presenting sign is leukocoria - white pupils on photos
  • tumours often show LOH
  • hypermethylation of promoter seen in 10% tumours
  • LoF mutations = almost complete penetrance
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

p53 is activated in response to _________

A

cellular stress (genotoxic or non-genotoxic)

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

in normal cells, p53 levels are kept low, how

A

The E3 ubiquitin ligase MDM2 degrades p53 protein.
p53 activates MDM2 expression
positive feedback loop to maintain low p53 expression

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

Under cellular stress conditions, p53 is ________

A

Phosphorylated & acetylated.

MDM2 can no longer interact and degrade p53 = increased levels of p53 - acts as TF to express downstream targets

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what proportional of colorectal cancers are associated with Lynch syndrome

A

3.5%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Lynch is also known as ________

A

Hereditary non-polyposis colorectal cancer (HNPCC)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What is the inheritance of HNPCC

A

AD. But AR at cellular levels - needs both alleles to be affected (2-hit hypothesis)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What genes are involved in HNPCC. What proportions

A

> 80-90% mutations in MLH1 and MSH2
7-10% in MSH6
< 1% in PMS2
3% due to deletions in 3’ end of EPCAM (upstream of MSH2)

24
Q

Tell me about FAP

A

Familial Adenomatous Polyposis

  • most common polyposis syndrome
  • APC gene (TSG)
  • AD
  • characterised by 100-1000s of adenomatous colonic polyps during 2nd decade of life
  • almost 100% risk of developing colorectal cancer if NOT treated (colorectomy)
  • colonoscopy screening occurs from age 10yr if have an APC mutation
  • mostly LOF
25
Q

Tell me about MUTYH associated polyposis (MAP)

A
  • AR
  • present similar to attenuated (mild) FAP
  • 10-100 polyps
  • 60% patients will develop colorectal cancer
  • MUTYH encodes a Base Excision Repair (BER) protein
  • mostly missense mutations
26
Q

What is the estimated lifetime risk of Breast Cancer in the UK

A

1 in 8

27
Q

What are the risk factors in Breast Cancer

A
  • family history (strongest)
  • reproductive behaviour
  • weight gain
  • alcohol consumption
  • HRT
28
Q

What is the function of BRCA1 and BRCA2

A
  • TSG
  • share NO homology with one another or other gene
  • play role in DNA repair (inc dsDNA break repair)
  • BRCA1 forms complexes with BARD1
  • BRCA1/BARD1 complex colocalised with BRCA2 and RAD51 at sites of DNA damage
  • Lose of BRCA1 or BRCA2 = results in defects in DNA repair
29
Q

BRCA1 / BRCA2 mutation status can inform clinical management decisions such as…..

A

1) Surgery. Mastectomy reduces risk of BS in BRAC1/2 +ve patients by 90%
2) treatment with PARP inhibitors

3) 10-20% of BRCA1/2 +ve patients are also Oestrogen Receptor (OR) positive and can be treated with Tamoxifen.
Tamoxifen competes with oestrodial to fill OR, causing reduction of gene transcription. Used as preventative measure in patients at risk of BC

30
Q

how does tamoxifen work

A

Many breast cancer cells are oestrogen receptor positive and response to oestrogen to grow / proliferate.
Tamoxifen blocks the OR binding site, presenting oestrogen from binding and thus preventing that cell proliferation signal.

31
Q

Neurofibromatosis type 1 is an autosomal _____ disorder caused by mutations in _________

A

AD

NF1 gene

32
Q

Presenting features of NF1 include

A

> multiple cafe-au-lait spots

> neurofibromas (small benign lumps compased of nerve cells and tough fibres)

33
Q

NF1 tumours are usually….

A

benign and affected the brain and spinal cord = pain

34
Q

Children with NF1 are at increased risk of developing?

A

a malignant myeloid disorder - JMML (juvenile myelomonocytic leukaemia)

35
Q

NF1 is a TSG, what types mutations can be found

A

80% truncating mutations.
50% de novo

note: NF1 is a negative regulator of RAS signalling, so loss of NF1 results in elevated RAS signalling

36
Q

NF1 shares degree of phenotypic overlap with a range of disorders grouped as ‘near-cardio-facial cutaneous syndromes (NCFC). What other syndromes are NCFCs

A
  • Noonan Syndrome
  • LEOPARD syndrome
    _ Legius syndrome
  • Costello syndrome
37
Q

why is blood testing not the best strategy for NF1?

A
  • NF1 gene has a high mutation rate (x10 higher)
  • as such somatic mutation (i.e. not inherited) is common
  • tend to perform direct testing via RNA / cDNA
38
Q

What are the classic presenting signs for NF2

A
  • bilateral vestibular schwannomas (acoustic neuroma)
39
Q

NF2 is a ________ gene. Mutations found are typically ________

A

Tumour Suppressor Gene

LoF mutations

40
Q

tell me about Tuberous Sclerosis

A

> Tuberous Sclerosis is AD, highly penetrance disorder, highly variable
Due to formation of hamartia and hamartomas (non-malignant tumours) in multiple organ systems
as hamartomas form in many systems, the impact and thus phenotype is variable

41
Q

Tuberous Sclerosis can affect which organs?

A

> CNS (90% patients)

  • seen as brain cortical tubers on neuroimaging
  • can result in epilepsy (80%), mild to severe ID and behavioural issues

> Skin (95% patients)

  • facial angiofibromas (butterfly red rash on face)
  • hypomelanotic macules - light patches on skin

> Kidneys (80% patients)
- can lead to renal lesions and bleeding - end stage renal disease possible

42
Q

What is the genetic cause of Tuberous Sclerosis

A

Germline mutations in either TSC1 (30%) or TSC2 (70%) followed by 2nd somatic mutation (inc. LOH)

TSC1 and TSC2 proteins form a complex functions as GTPase activating protein (GAP). BOTH proteins are needed for normal function, so loss of either = TS

note: this TSC1/TSC2 complex restricts activation of mTORC1 (a protein kinase which regulated protein synthesis, cell growth and proliferation)

43
Q

Signalling pathways are typically disrupted in many cancers. What are the 3 main signalling pathways?

A

1) MAPK (mitogen-activated protein kinase)
2) WNT
3) PI3K

44
Q

Describe the basic signalling pathway for MAPK

A

Stimulus > MAPKKK > MAPKK > MAPK > transcription factor.

45
Q

What are the 4 main MAPK pathways

A

1 - ERK (activated by growth factors)
2 - JNK
3 - p38
4 - ERK5

2,3,4 activated by stress

46
Q

Provide an example of the ERK pathway

A

ERK - extracellular signal-regulated kinase MAPK pathway

> STIMULUS: ligand bound to EGFR
> activation of B-RAF
> activation of MEK1
> activation of ERK1
> activation of Transcription factors
47
Q

Name the 2 WNT signalling pathways

A

canonical (CTNNB1-dependant) and non-canonical (CTNNB1-independant)

note: CTNNB1 = B-catenin

48
Q

Activation of WNT pathway drives_______

A

B-catenin into nucleus to activate WNT target gene expression.

49
Q

Give an example of a gene which can be mutation in cancer and impacts WNT signalling

A
  • APC gene
  • APC has a role in degrading B-catenin so loss of APC = elevated levels of B-catenin = increase expression of WNT regulated genes
50
Q

The PI3K pathway works downstream of ________

A

Receptor tyrosine kinases and G-protein coupled receptors.
They transduce extracellular signals (e.g growth factors or cytokines) into intracellular signals by generating phosholipids which activates the Serine/threonine kinase ART pathway

51
Q

Describe the basic signalling pathway for PI3k

A

> Inositol + P = PIP
PIP + P = PIP2
PIP2 + P = PIP3

52
Q

what are the components of PI3k signalling pathway?

A

> Receptor Tyrosine Kinase
PI3 kinase (e.g. PIK3CA gene)
AKT - serine/threonin kinase downstream mediator of PI3K
PTEN - acts as a negative regulator of the PI3K pathway (often found downgraded in cancers)
mTOR - plays role in cell growth & proliferation

Receptor Kinase > PI3K > AKT > mTOR

53
Q

MLH1 hypermethylation is found in 15% of sporadic HNPCC cancer cases. How can we test for this. What else can be detected?

A

> MS-MLPA
detects methylation state at 5x sites in MLH1 promoter
also at 4x sites in MSH2 promoter (used to confirm a 3’ EPCAM deletion)

54
Q

What is the significance of EPCAM in HNPCC?

A

> deletions in the 3’ end of the EPCAM gene are found in 3% of HNPCC cases
EPCAM is upstream of MSH2. Deletions of the end of EPCAM can ‘run into’ the MSH2 coding region.
EPCAM deletions can run into the MSH2 promoter or even into the MSH2 coding sequence (abolishing MSH2 start site!)
thought to account for 25% of MSH2 IHC -ve cases with no MSH2 germline mutations

55
Q

In patients with abnormal / absent MLH1 IHC results, NICE guidelines recommend testing for the BRAF V600E mutation first, before MLH1 hypermethylation. Why?

A

BRAF mutations are associated with Sporadic cancer and so can help distinguish between sporadic or inherited testing (i.e. is sporadic, don’t proceed with HNPCC testing)

FRCPath Genomics (12 decks)

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