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Life Protection > Oncogenesis > Flashcards

Oncogenesis Flashcards

1
Q

What is cancer?

A

A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems

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2
Q

What are the 4 main stages fo carcinogenesis?

A
  • initiation
  • promotion
  • progression
  • malignant conversion
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3
Q

What happens in the INITIATION of carcinogenesis?

A

interaction of carcinogen with DNA

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4
Q

What happens in the PROMOTION of carcinogenesis?

A
  • selective growth advantage (free radicals)

- early pre-cancer (adenoma) reversible

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5
Q

What happens in the PROGRESSION of carcinogenesis?

A
  • enhanced cell division

- later pre-cancer (late adenoma), reversible

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6
Q

What happens in the MALIGNANT CONVERSION of carcinogenesis?

A
  • cancer, not reversible
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7
Q

Which tumour suppressor gene is reliant for colorectal cancer?

A

adenomatous polyposis coli (API)

expression associated with later stage tumour

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8
Q

What is a carcinogen?

A

substances and exposures that can lead to cancer

N.B chemo is also carcinogenic

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9
Q

What are the 3 types of carcinogens?

A
  • chemical
  • physical
  • viral
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10
Q

What are examples of chemical carcinogen?

A 
benzene
acylating agents (chemo)
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11
Q

What are examples of physical carcinogens?

A

X-rays
UV light
alpha particles

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12
Q

What are examples of viral carcinogens?

A
  • hep B

- HPV

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13
Q

What are examples of hereditary cancer predisposition syndromes?

A

Li-Fraumeni syndrome (TP53 loss of function)

Down’s syndrome (trisomy 21)

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14
Q

What are the 2 main types of physical carcinogens?

A
  • ionising (gamma, X-rays)

- non-ionising (UV ligjht)

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15
Q

What are proto-oncogenes?

A

normal cellular genes which regulate cell growth and/or division and differentiation

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16
Q

What is an oncogene?

A

A porto-oncogene that has been activated by mutation or overexpression

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17
Q

What is an eg of a point mutation creating an oncogene?

A

point mutation creating K-RAS in lung cancer

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18
Q

What is an eg of a gene amplification creating an oncogene?

A

c-myc

breast cancer

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19
Q

What is an eg of a chromosomal translocation creating an oncogene?

A

creation of fusion protein

BCR-ABL (chronic myeloid leukaemia)

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20
Q

How many alleles/inheritance is required to mediate effects of an oncogene?

A

dominant effect

only one altered allele is needed to mediate pathogenic effects

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21
Q

What does the Her2/neu/ERBB2 gene encode?

A

part of the human epidermal GF receptor

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22
Q

How does the Her2 receptor function?

A

Her2 = tyr-kinase receptor

binding of GFs (e.g. EGF)

confirmational change to activate receptor

receptor dimerisation needed for function

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23
Q

What is the link between Her2 and cancer?

A
  • HER2 is amplified in ~20% of invasive breast cancers

- associated with aggressive disease and poor prognosis

24
Q

What is the nature of the Her2 gene dysfunction?

A

no point mutation in coding gene
OVEREXPRESSION of Her2 gene
resulting in high abundance of Her2 receptor on PM

25
Q

What targeted therapies are available for Her2 tumours?

A

Monoclonal antibodies:
Trastuzumab (Herceptin) and Pertuzumab

Only effective in HER2+ cancers

These agents disrupt the dimerisation of the Her2 receptors that result in activation of the downstream signalling cascade

26
Q

What is the BCR-ABL1 translocation contain?

A

BCR: protein acts as a guanine GEF for Rho GTPase

ABL1: protein tyrosine kinase receptor (activity is controlled by autophosphorylation = inhibition).

27
Q

How does BCR-ABL1 mediate pathogenic effects?

A

BCR-ABL1 protein has constitutive/unregulated protein tyrosine kinase activity

  • proliferation of progenitor cells in absence of GFs
  • decreased apoptosis
  • decreased adhesion to BM stroma
28
Q

What kind of gene is ABL1?

A

Proto-oncogene encoding a cytoplasmic protein

29
Q

What is the Philadelphia chromosome?

A

BCR-ABL1 translocation

Found in 95% of CML cases

30
Q

What does presence of the Philadelphia chromosome indicate?

A

(BCR-ABL1 translocation)

  • detection of minimal residual disease
31
Q

What treatments can be used in BCR-ABL1 positive tumours?

A

drugs that specifically inhibit BCR-ABL1

e.g. Imatinib (inhibitor)

32
Q

What are the Myc proto-oncogenes?

A

encode for transcription factors

33
Q

What do pathogenic alterations in c-myc cause?

A
  • gene retrovirus activation
  • amplifications
  • translocations
34
Q

How are c-Myc oncogenes produced?

A

integration of viral DNA into the host genome

translocation adjacent to c-Myc

Overstimulaton at promoter

uncontrolled cell proliferation and so tumorigenesis

35
Q

What are tumour suppressor genes?

A

encode proteins that maintain checkpoints and control genome stability

36
Q

What mechanisms do tumour suppressor genes use to control the cell cycle?

A
  • Repair of DNA damage (MLH1, BRCA1/2)

- Apoptosis (TP53)

37
Q

What is the main function of tumour suppressor genes?

A
  • inhibit replication

- Inhibit proliferation of damaged cells

38
Q

What is Knudson’s two-hit hypothesis?

A

most LoF mutations that occur in tumour suppressor genes are recessive in nature

A second hit (homozygous recessive) is needed to disrupt gene function

39
Q

What process favours the acquisition of DNA mutations?

A

KO of DNA repair function

usually of 1 or more genes

sequential process

40
Q

What results from defects in DNA repair mechansims?

A
  • genomic instability
  • (accelerated) activation of oncogenes
  • loss of tumour suppressor genes
41
Q

What do tumour resulting from inherited defects in DNA repair genes imply about the mutational load?

A

high mutational load

i.e. due to the the 2-hit hypothesis and recessive nature of tumour suppressor genes

lots of mutations are needed to initiate tumour formation as a result

42
Q

What is the function of the BRCA1/2 genes?

A

to repair double stranded DNA breaks

43
Q

What proteins repair ssDNA breaks?

A

PARP proteins

44
Q

Why do new Rx target PARP proteins for breast cancer?

A

PARPi = new Rx in BRCA1/2 carriers. Inhibit the repair of ssDNA breaks.

This means that there are no DNA repair mechanisms (dsDNA or ssDNA) and so cells die by apoptosis

45
Q

What are the main types of PARPi?

A
  • Olaparib
  • Rucaparib
  • Niraparib
  • Talazoparib
46
Q

What is the direct function of p53?

A

protein which works at the G1/S checkpoint

binds to p21 (a CDK inhibitor)

47
Q

What tumour suppressor proteins work at the G1/S phase checkpoint?

A
  • p53 (p21)

- Rb-E2F

48
Q

What are the functions of p53?

A
  • detects cellular stress, especially DNA damage
  • induces G1/S and G2/M cell cycle arrest
  • if this fails, apoptosis is triggered
49
Q

How is TP53 implicated in cancers?

A

> 50% of cancers cause TP53 mutations

In some cancers, TP53 mutations correlate with pathological stage of cancer (can indicate later/more severe stage)

50
Q

What is Li-Fraumeni syndrome?

A

mutations in TP53 causing increased risk for cancers

> 70% of families with this will have a mutation in TP53

51
Q

Which cancers does Li-Fraumeni syndrome predispose you to?

A
  • breast
  • leukaemia
  • lung
  • pancreas
  • sarcoma
  • Wilms
  • Gliobastoma
52
Q

What is Wilms tumour?

A

nephroblastoma
rare kidney cancer, highly treatable
prevalent in children

53
Q

What is RB1?

A
  • tumour suppressor “gatekeeper”
  • acts at G1/S phase transition, preventing cell cycle and growth until all criteria are met for it to proceed
  • inactivated by phosphorylation
54
Q

How is RB1 related to malignancy?

A
  • malignant tumours of eye originating from the retina
  • occurs in 1:20,000 childen
  • 90% occur <5yo
  • Rx: surgery and radiotherapy
  • 98% cases cured
55
Q

What is SPORADIC retinoblastoma?

A

(no FMHx)

  • 60% of cases
  • single tumour
  • unilateral
56
Q

What is FAMILIAL retinoblastoma?

A
  • 30% of cases
  • FMHx
  • multiple tumours
  • bilateral
57
Q

What are the main challenges with oncogenesis?

A

cancer caused by accumulation of multiple mutations

tumour heterogeneity

diverse physiological pathways

tissue specificity

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