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BOD Lent > Cancer > Flashcards

Cancer Flashcards

1
Q

What is meant by gene changes?

A
  1. Mutations - any kind of alteration of DNA sequence
  2. Epigenetic changes - aberrant DNA methylation or histone modification
  3. Tumour viruses - bringing extra genes into cells

Adult cancers will usually have more than 10 ‘gene changes’

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2
Q

Metastasis

A

Formation of new colonies of tumour in other parts of the body, by the seeding of cells into the circulation. Such a colony is a metastasis, and the process is also called metastasis.
- Original tumour is called Primary Tumour and the metastasis may be called a Secondary Tumour

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3
Q

Malignant tumours

A

Capable of metastasis
- Tumour doesn’t have to have formed any metastases to be malignant - as formation is very slow and inefficient and may not have happened yet

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4
Q

Benign tumour

A

Incapable of metastasis

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5
Q

Morphological differences between malignant and benign tumours

A
  • Benign: Confined to original site in the body, clearly defined boundaries, can be physically separated from surrounding tissue, surrounded by a capsule of connective tissue
  • Malignant: Ragged edges, infiltrating into surrounding tissue - infiltration is known as invasion. May lose differentiation
  • Also differences in nuclear size and shape
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6
Q

Clonal expansion

A

A cell acquires a mutation and over time its progeny compete with neighbouring cells so that they take over more than normal share of tissue

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7
Q

Why might a tumour display heterogeneity?

A

Lump of tumour may not just contain latest clone but also also preceding clones and dead-end branches of the evolutionary tree.

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8
Q

Which gene is overactive in breast cancers?

A

CCND1/Cyclin D1 gene due to many extra copies of the gene (gene amplification)
- p16/INK4 inhibits kinase, so it must be inactivated; both copies are deleted

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9
Q

Leiomyoma

A

Benign smooth muscle tumour of the uterus

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10
Q

Leiomyosarcoma

A

Invasive smooth muscle cancer of the uterus

- Layers of tumour and normal uterine muscle are intermingled

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11
Q

Oncogene mutations

A

Overactivity mutations - Dominant e.g. oncogenes CDK4/CyclinD1

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12
Q

Tumour suppressor gene mutations

A

Loss of function mutations - Recessive e.g. RB1

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13
Q

What is required for adenoma formation?

A

Mutation in either APC or beta-catenin; mutating either gene has much the same effect so these are alternatives –> have antagonistic effects one is an oncogene and the other is a tumour suppressor

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14
Q

Sequence of mutations in the Vogelstein model of Colon Cancer

A
  • APC/ beta-catenin
  • CDC4/ CIN
  • KRAS/ BRAF
  • PIK3CA/ PTEN
  • p53/TP53 or BAX
  • SMAD4 or TGF-beta
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15
Q

Genetic instability?

A

Cells are more prone to undergo mutation. Cancers need many genes to be mutated, and acquiring these mutations is accelerated in cells that are ‘genetically unstable’. Due to damages to the DNA maintenance machinery.
- Arises from defects in DNA repair or defects in replication and mitosis

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16
Q

Mutations that inactivate mismatch repair result in…

A
  • Micro-satellite instability
  • Higher point mutation rate
  • 15% of sporadic colon cancers, almost normal chromosomes but have sequence instability due to inactivation of MLH1/MLH2. 100-fold increase in rate of small mutations; single base changes + frameshift due to elongation/shrinkage of repeats.
  • Mismatch repair deals with mismatched bases and loops generated by polymerase slippages. Loops persists causing shrinkage or expansion of short repeats known as MICRO-SATELLITES
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17
Q

Tumour B (85%) in colon cancer is characterised by…

A
  • Chromosomal instability (CIN), despite having a normal point mutation rate, due to mutations in managing or repairing chromosomes
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18
Q

Failure to repair DNA damage

A

Sequence instability - MLH1

Chromosome instability - BRCA1, BRCA2

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19
Q

Errors in replication or mitosis

A

Sequence instability - pol epsilon

Chromosome instability - defective spindle attachment

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20
Q

Main categories of DNA repair

A
  • Base excision
  • Nucleotide excision
  • Non-Homologous End Joining
  • Homologous Recombination
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21
Q

What causes inactivation of MLH1?

A

Epigenetic change; methylation of DNA of its promotor

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22
Q

Homologous recombination

A

Repair double strand breaks - relies on there being two copies of the genome, as it uses the sister chromatid to re-synthesise the broken bit. BRCA1 helps start reaction, BRCA2 prepares single strand ends for base pairing to other helix.
- In breast cancers, absence of BRCA1/2 means that homologous recombination is defective –> chromosome instability

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23
Q

Mutations directly affecting DNA synthesis

A

Mutations in DNA polymerase epsilon proof-reading domain; high error rate. Found in a few percent of colon tumours

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24
Q

Defects in mitosis?

A

Errors in chromosome segregation can result in chromosome instability. In some cancer cells, chromosomes sometimes get left behind or broken during anaphase.

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25
Q

Growth control genes?

A

APC, RB1

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26
Q

Genetic instability genes?

A

MLH1, MSH2, BRCA2

27
Q

Adenomatous Polyposis/ Familial Adenomatous Polyposis

A
  • Rare
  • ~1000 polyps, and then colon cancer
  • Mutation in APC
  • 80% of sporadic colorectal cancers also have APC mutations
28
Q

Lynch syndrome/ Hereditary non-polyposis colon cancer

A

1% of colon cancers
Colon cancers without lots of polyps
Inherit mutation in mismatch repair gene e.g. MLH1/MSH2
15% of sporadic cancers have the same mutation

29
Q

Hereditary predisposition to Breast Cancer

A

5% of breast cancer
50-80% lifetime risk of breast cancer
about half of these inherit mutation in BRCA1/2
- BRCA2 is a component of HR double strand repair pathway

30
Q

Knudson two-hit hypothesis

A

The idea that typical tumour suppressor genes require two mutations to inactivate both copies.

31
Q

How can we demonstrate that genetic instability is independent to growth control and malignancy

A

Cancer with restored BRCA2 still kills patient –> BRCA2 mutation is not needed for malignancy

32
Q

Hallmarks of Cancer?

A
  • Independence of growth stimulating signals
  • Resistance to growth inhibitory signals
  • Differentiation block
  • Resistance to apoptosis
  • Immortality
33
Q

Wnt Signalling Pathway

A
  • Almost all colorectal cancers have a mutation in it; either in APC, beta-catenin or Tcf transcription factor.
  • APC inactivation is much more frequent
  • Beta-catenin acts with Tcf transcription factor in the nucleus in order to drive cell proliferation/ clonal expansion. APC forms a complex that degrades beta-catenin, Wnt signalling prevents degradation.
  • Pro-proliferative mutations include inactivation of APC or activation of beta-catenin
34
Q

Receptor tyrosine kinases and downstream signalling pathways

A

Receptor tyrosine kinase autophosphorylate and recruit signalling pathways. ERBB/EGF-receptor family is composed of ERBB/EGF and ERBB/HER2 receptors. 2 downstream signalling pathways:

1) MAPKinase pathway > RAS and RAF > Proliferation + survival
2) PIP3 Pathway = PI3Kinase converts PIP2 to PIP3 which activates AKT kinases. PTEN reverses PIP3 to PIP2. Acts to reduce apoptosis

35
Q

TGF beta pathway

A

Growth inhibitory for epithelial cells. TGFbeta growth factors signal via transmembrane receptor to SMAD family, which carry signals to the nucleus.
- Mutations in TGFbetaRII, SMAD4, SMAD2 are common in colon cancer

36
Q

Leukaemias in differentiated lymphocytes

A

Chronic B-lymphotic leukaemia + myeloma

37
Q

Leukaemias in stem cells

A

Acute leukaemia

38
Q

Stem cells leukaemia that can show differentiation

A

Chronic myeloid leukaemia. Note that leukaemias with blocked differentiation are more aggressive than differentiating ones.

39
Q

Apoptosis

A
  • Limits proliferation and removes damaged or stressed cells. Anti-apoptotic mutations include inactivation of BAX or p53
  • BAX is a major mediator of apoptosis, unregulated by p53. BAX antagonises its relative BCL2 and mediates permeabilisation of mitochondrial membrane + activation of caspases.
  • Vogelstein model suggests that mutations in BAX and p53 may be alternatives in colon cancer.
40
Q

BCL2

A

Anti-apoptotic relative of BAX

41
Q

Hayflick Limit and Cancer

A

Normal human somatic cells in culture would only divide a fixed number of times before entering cell cycle arrest, a response known as senescence - determined by telomere length (TTAGGG repeats at the ends of chromosomes)
- Tumours cells grow indefinitely as they have turned on telomerase. Point mutations in the promoter of telomerase can activate expression in 70% of melanomas and 10-20% of randomly selected cancers.

42
Q

Examples of stress responses causing senescence and how they are overcome

A
  • Shortening of telomeres as cells replication
  • DNA damage
  • Strong activation of oncogenes - expressing mutant RAS in otherwise normal cells = ‘oncogene induced senescence’

Mutation of p53, with or without mutation of RB1, will alleviate these stress responses. HPVs associated with cervical cancer have proteins that overcome senescence by inactivating RB1 and p53

43
Q

p53 - a hub for stress signals

A

P53 can signal the cell to arrest cell cycle or go into apoptosis. It is a mutant in around 1/3rd to 1/2 of all human neoplasms.
-P53 levels can be raised within minutes; as it is continuously being translated and degraded - so blocking degradation causes levels to rise rapidly.

44
Q

Angiogenesis

A

In order for a tumour to grow beyond a certain size, it needs to develop a blood supply, by sprouting of new branches from adjacent capillary network. Unsure of whether angiogenesis is a tumour specific property, or a normal response to anoxia.

45
Q

How metastases form?

A

Tumour cells will migrate through connective tissue - cells slip through pre-existing spaces between cells, along collagen fibres, and eventually into lymphatics and veins.

46
Q

What determines metastasis and describe the process?

A
  • Some intrinsic property of the tumour

- Escape of cells into vessels, survival in circulation, escape out of vessels into tissue, and the survival and growth

47
Q

Which step is critical to metastasis?

A

Major barrier is survival and growth in the distant site.

48
Q

What causes the step from malignancy to metastasis?

A

Requires little or no additional genetic change - it is a are stochastic process

49
Q

Are cells from metastases any more metastatic than cells from the primary tumour?

A

No, this indicates that most primary tumour cells are capable of metastases. Although many tumour cells enter circulation, only few are successful in establishing metastatic colonies.

50
Q

Driver mutations

A

Mutations that give a cell selective advantage - and are interspersed by random ‘passenger mutations’

51
Q

MYC

A

Oncogene + transcription factor that powerfully up regulates many genes involved in proliferation and is widely activated

52
Q

ERG

A

Transcription factor that may control differentiation; fused in prostate cancer

53
Q

Chromatin modifiers

A

Proteins that modify histones in order turn genes on and off, e.g. MLL is a histone methylase and is fused to other genes by chromosome translocations in leukaemia.

54
Q

E-cadherin

A

Cell adhesion molecule; inactivated in breast cancers

55
Q

Mutations in isocitrate dehydrogenase (IDH1)

A

An enzyme in the Krebbs cycle; mutated in some brain cancers.
- Mutation changes enzyme specificity to make hydroxyglutarate - main effect is to block DNA demethylation and block differentiation.

56
Q

Sequence level mutations

A

Change to a single base pair

Indels; small insertion or deletion - usually give truncated proteins due to frameshift

57
Q

Structural changes (large scale changes)

A
  • Deletion
  • Duplication
  • Amplification
  • Chromosome translocations
    Cell acquires a large number of copies of an oncogene by repeated duplication of a segment of the genome
58
Q

Gene fusion

A

Rearrangement of large chunks of DNA create a new gene by joining two genes together to create gene fusion; most powerful cancer mutation. Chromosome translocations are particular famous for doing this - discovered first in leukaemia.

59
Q

Illumina sequencing

A

Millions of DNA fragments are attached to a glass slide and sequenced simultaneously (massively parallel sequencing)

60
Q

Cytogenetics

A

Study of chromosomes by microscopy. Cells are arrested by metaphase + chromosomes spread and stain. This can show chromosome translocation and some deletions or inversions.

61
Q

Philadelphia chromosome

A

Reciprocal translocations between chromosome 9 and 22 found in chronic myeloid leukaemias. Smaller chromosome is called the Philadelphia chromosome.

62
Q

FISH

A

Fluorescence-in situ hybridisation. Cytogenetics enhanced by FISH; DNA is labelled with fluorescence and hybridised to metaphase chromosomes. DNA from a chromosome can be labelled or a small segment of genome can be labelled.
- Used clinically to detect amplification of HER2

63
Q

What gene is amplified in lung tumours?

A

N-MYC

BOD Lent (4 decks)

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