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BMS379 - Cancer Biology > L1 - Genomic Instability > Flashcards

L1 - Genomic Instability Flashcards

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1
Q

Describe the principle of cancer arising from mutation

A

Heritable variation leads to selection which then leads to a change in allelic frequency

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2
Q

Describe how allelic frequency changes in canccer

A

Initially the cell has a single mutation - over time cell proliferation leads to even more mutations arising and these have increased allelic frequency

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3
Q

What is the first hallmark of cancer

How was it discovered

A

Genomic instability

Systematic sequencing of cancer cell genomes

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4
Q

What can instability of genomes be represented on

A

Cytogeneitic maps - circos plots

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5
Q

Describe how tumour cells harbour enormous genomic instability

A

There is a huge mutational burden #24000 mutations
Mutations within the whole tumour
Individual cells vary in their genomic composition

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6
Q

Describe the hierarchy of alterations that occur in cancer cell genomes

A

Interchromosomal strucutural varsiations
Intrachromosomal strucutural variations
Loss of heterozygosity/allelic imbalance
Copy number variation
Single nucleotide variation

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7
Q

How are cancer cell genomes sequenced?

A

Massive parallel sequencing

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8
Q

Describe the process of massive parallel sequencing

A

Shear genomic DNA to 100bp ss fragments
Ligate chemically at the end to a known adaptor sequence
Chemically attach chimeric DNA to solid chip surface
Introduce an anchor which anneals to the adaptor sequence
Introduce probes each labelled with a different flurophore
Only the probe perfetly complementary to the genomic DNA will perfectly anneal in presence of DNA ligase
Raise temp - if not ligated probe will fall off
Spot on chip will be the same colour as that of the flurophore
Specificity of DNA ligand enablees multiple related probes

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9
Q

Describe how the specificity of DNA enables configuration of multiple related probes

A

Start with using position -1 probes - then can use position -2 and -5 probes

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10
Q

How is the problem of sequence depth addressed

A

Usiig offset anchors with variable length offsets

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11
Q

What is mean by HUGE parallel seqeucning

A

Huge arrays are used - many many chips used

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12
Q

Describe how the issue of signal strength is addressed

A

MORE than one molecule is used

DNA polymersase is used to amplify circular lengths which produces DNA nanoballs

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13
Q

What does CIN stand for

A

Chromosomal instability

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14
Q

What is CIN

A

The inability to maintain the correct number and gross composition of chromosomes

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15
Q

What is numerical CIN

A

Aneuploidy

The wrong number of chromosomes

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16
Q

What is strucutural CIN

A

Gross compositional failure in chromosomes

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17
Q

What can CIN be visualised with

A

Chromosomal painting

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18
Q

Describe the process of chromosome painting

A

Using probes that stain each chromosome a different colour for each chromosome
Can see through colour rearrangement if chromosomal rearrangement has occured

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19
Q

The philadelphia chromosome leads to what clinical condition

A

Chronic myeloid leukaemia

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20
Q

What is the fusion protein formed in the philadelphia chromosome

A

BCR-ABL fusion protein

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21
Q

What is the function of the BCR-ABL fusion protein

A

It encodes a consituitively active tyrosine kinase

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22
Q

How can the Philadelphia chromosome be visualised

What is seen

A

Using FISH
Flourescent in-situ hybridisation

Can see part of chromsomes 9 fused to 22 and part of 22 fused to 9

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23
Q

What is copy number variation an example of

A

Chromsomsal instability

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24
Q

Describe an instance where copy number variation is observed in cancer

A

N-myc is amplified in neuroblastoma

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25
Q

How can copu number variation be visualised

A

Use probes to the gene that you think has be amplified - would see many spots

Compare to a control

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26
Q

What is FAp

A

Familial adenomatous poplyposis

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27
Q

What is the gene that is mutated in FAP

A

The APC gene

This is a recessive mutation

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28
Q

Where does FAP occur

A

In the intestinal crypt

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29
Q

Describe NORMAL signalling in the intestinal crypt

A

Stem cells at the bottom of the cryp
B catenin signalling causes the proliferation and upwards movement
Towards the top of the crypt B-catenin is turned OFF leading the cell cycle arrest and the differentiation of these cells

30
Q

Describe how FAP may occur

A

Failure to turn OFF B-catenin signalling at the top of the crypt leads to all of the cells at the top having a progenitor like phenotype and the formation of a polyp

31
Q

Describe the Wnt signalling cascade - in the presence of Wnt

A

Wnt binds frizzled which activates dishevelled
Dsh inhibits GSK3B which releases B catenin from the Axin-APC-GSK3B complex
B catenin translocates into the nucleus binding Tcf/Lef causing transcription of Wnt target genes

32
Q

APC is a

What its normal function

What happens if this is not present

A

Tumour suppressor gene

Normally part of the complex that in the absence of Wnt, binds and prevents the nuclear translocation of B-catenin

When mutant there is no way of stopping B-catenin entering the nucleus and thus this pathway is constituitively on

33
Q

What is MIN

A

Microsatellite instability

Refers to variation of a single nucleotide

34
Q

What are microsatellites

A

Variable length dinucleotide repeats

35
Q

Why are microsatellites vulnerable to DNA damage

A

Since mismatches are able to occur easily during replication

36
Q

MIN is a consequence of

A

Unrepaired DNA damage

37
Q

What are two ways in which unrepaired DNA damage can cause MIN

A

Deamination of C

Depurination of A

38
Q

Deamination of C

A

Loss of the amino group
C–>U
When replicated pairs with A
Introduces a point mutation C-G ==> U-A

39
Q

Depurination of A

A

Loss of the (big) purine group
When replicated one of the strands in a base short
(A-T nucelotide has been deleted)

40
Q

In both the deamination of C and depurination of A what does MIN rely on

A

The replicaition before DNA damage can be recognised

41
Q

What sort of mutations precipate MIN

A

Mutations in the mismatch repair proteins

42
Q

Describe a clinical condition underpinned by a mutation in a mismatch repair pathway

A

HNPCC (Lynch Sundrome)
Hereditary non-polyposis colon cancer

Loss of function in MLH1 PMS2 MSH2 MSH6

43
Q

What are MLH1 PMS2 MSH2 MSH6 involved in

A

Mismatch repair pathways

44
Q

If the geneomic instability is a feature of carcinogenesis then what does this imply regarding the importance of mutations

A

Many of the mutations will be irrelevant

45
Q

What are the two classed of mutations

A

Driver

passenger

46
Q

Describe how driver mutations were identified

A

Compare viral oncogene sequences with human homologues

Then use assays of transformation to identify oncogenes in mouse modesl

47
Q

Describe how transformed cells can be identified in the dish

A

Display both anchorage and growth factor independent growth

48
Q

Describe how you would test if a gene is an oncogene in mice

A

Inject cellls that have been trasnformed into a mouse model

Should see tumour growth if it is an oncogene

49
Q

Many forms of inherited cancer involves single gene mutations.

What gene is linked to retinoblastoma what does this encode

A

Rb

Transcriptional repressor

50
Q

Many forms of inherited cancer involves single gene mutations.

What gene is linked to Li Fraumeni what does this encode

A

P53

DNA damage response protein

51
Q

Many forms of inherited cancer involves single gene mutations.

What gene is linked to Wilm’s tumour what does this encode

A

Wt-1

Transcriptional regulator

52
Q

Many forms of inherited cancer involves single gene mutations.

What gene is linked to Gorlins syndrome what does this encode

A

Pyc

Membrane receptor signalling

53
Q

Many forms of inherited cancer involves single gene mutations.

What gene is linked to Breast cancer what does this encode

A

BRCA-1

DNA repair and recombination

54
Q

Many forms of inherited cancer involves single gene mutations.

What gene is linked to FAP what does this encode

A

APC

B catenin signalling transducer/regulator

55
Q

The early attempts to identify driver mutations favoured what type of genes

A

Genes promoting proliferation and clonal expnsion

56
Q

What techniques were used to identify driver mutations

A

Homology to viral oncogenes
Cytogenetics
Differential gene expression

ALL COMBINED WITH TESTING IN A MODEL SYSTEM

57
Q

What is progressive lymphoma associated with

How can this be visualised

A

Increased Myc expression

See using Western blot

58
Q

What is NGS

What does it allow

A

Next generation sequencing technologies

Allows us to identify mutations

59
Q

When using NGS to identify driver mutations what was the hypothesis

A

Driver mutations are likely to occur frequently while passenger mutations are likely to occur randomly

60
Q

What were some of the genes commonly seen to be mutated in the 131 colon cancers that were sequenced

A 
APC
K-Ras
P53
PIK3CA
FBXW7
61
Q

Genes commonly mutated are seen as what on the chromosome 1-X, gene position, frequency (x,y,z) plot

A

Mouthains

62
Q

Hills and mountains …

A

Are genes that are frequently mutated and thus these are likely to be dirver mutatiosn

63
Q

Hillocks (invisible)

A

Occur randomly with no pattern and thus are likely to be passenger mutations

64
Q

In any given cancer around how many driver mutations are there

A

around 15

65
Q

What can be seen in terms of mountains, hills and hillocks if we compare two colorectal cancer side by side

A

Some common mountains
Very few common hills
Many disparate hullocks

66
Q

Describe what is seen when plotting cancer against age

A

That the probability is the number of genetic changes that are required to cause cancer (lots of changes would mean that cancer would be very rare)

67
Q

Describe the mathematical model related probability of getting cancer with the number of genetic changes that need to occur

A

LogP(T) = nLogA + constant

68
Q

LogP(T) = nLogA + constant

What is the slope

A

Slop is the indication of what needs to occur

Steep slope means that many changes have to occur and the probability is low

69
Q

What does bioinformatics allows us to look at with regards pathways

A

Looks at the links between various genes

Each line = some link and suggests that genes are here involved in the same pathway

70
Q

In different types of cancers ______

A

Different parts of the pathway are targetted

e.g. some mutations more common in colon cancer and others more common in breast cancer

BMS379 - Cancer Biology (11 decks)

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