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Pathology > precursors, carcinogenesis... > Flashcards

precursors, carcinogenesis... Flashcards

1
Q

what precancer stages are seen in the cervix/vulva/anus/bronchus?

A

intra-epithelial neoplasms/lesions.
non invasive. stay on epithelial side of the BM.
cervix = cervical/squamous inta-epithelial neoplasia (uk/us classification)
CIN1 = low grade SIL, CIN2 and 3 = high grade SIL

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2
Q

cytology of intraepithelial neoplasms.

A
  • abnormal nuclei
  • abnormal mitosis,
  • loss of nuclear polarity
  • loss of differentiation.
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3
Q

why are pre-cancerous changes imp?

A
  • suggest biologically a sequential progression from CIN to invasive cancer.
  • clinically important as they can be detected (cervical smears or liquid based cytology).
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4
Q

pre cancerous changes in breast tissue?

A

Ductal carcinoma in situ (DCIS)
may persist for many years before cancer.
excess no of neoplastic epithelial cells within the enlarged ducts or groups of small ducts causing dilation.
-pleomorphism, hyperchromasia, loss of differentiation.

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5
Q

how many women are affected by breast cancer in developed countries

A

about 1 in 11

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6
Q

adenocarcinoma incidence

A

second commonest cancer in developed countries, over 90% thought to be preceded by an intraepithelial phase called an adenoma.
screening for bowel cancer and adenomas started in 2007-2009 in the UK.

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7
Q

describe large intestine adenomas

A

all adenomas have dysplastic glandular epithelium and this is graded ow to high. high grade regions can evolve into invasive adenocarcinoma.

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8
Q

importance of large intestine adenomas?

A

a sequence of changes can be traced.
adenomas (polyps) are not uncommon, particularly in older people.
invasive cancer often develops from an adenoma as a result of progression from dysplasia to cancer.
“adenoma-carcinoma” sequence. low grade - high grade dyplastic epithelium - invasive carcinoma.

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9
Q

what are carcinogens/oncogens?

A

agents which induce cancer

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10
Q

what is carcinogenesis/oncogenesis?

A

the process of cancer induction

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11
Q

what are the classes of carcinogen

A

1 - chemical - molecules
2 - physical - UV, ionising radiation
3 - biological - viruses, bacteria, parasites

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12
Q

how is cancer (as a multi-step process) studied?

A
  • animal models
  • in vitro carcinogenesis
  • replicative senscence, immortalisation and telomeres.
  • inherited cancers in humans
  • molecular genetic analysis of cancers and their precursor lesions.
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13
Q

2 potent carcinogens in tar

A

3-benzpyrene

3’methylcholanthene

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14
Q

5 principles of carcinogenic action

A

1 - dose response
2 - latent period (the length being dose dependent)
3 - threshold dose - although if a secondary non-carcinogenic stimulus is applied afterwards that is able to promote growth to the site of a sub-threshold dose, tumours develop.
4 - initiation and promotion
5 - progression (a thrid stage after initiation and progression)

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15
Q

2 stages of carcinogenesis

A

1 - initiation - irreversible change of a normal cell to a potentially cancerous one. Carcinogens are mutagens.
2 - promotion - a process which permits clonal amplification of the initiated cell. promoters are not carcinogens, they just induce proliferation. a benign neoplasm forms.

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16
Q

what is progression in carcinogenesis?

A

a potential 3rd stage of the model. acquisition of further mutations within the neoplastic clone to drive progression to malignancy.

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17
Q

what is cell transformation

A

the change in phenotype and behaviour of a cell.

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18
Q

what is replicative senscence

A

the fact that cells can undergo only a defined number of cell divisions in tissue culture before cycle arrest and apoptosis.

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19
Q

what the hayflick number

A

the number of divisions a cell can undergo before apoptosis.

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20
Q

cell immortalisation in humans (long lived) vs mice or rats

A

very rarely undergo spontaneous immortalisation in tissue culture

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21
Q

name some viral oncogenes that can cause immortalisation.

A

SV40 T
adenovirus E1A and E1B
HPV 16 E6 and E7
chemical carcinogens rarely do this.

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22
Q

what is the cause of immortalisation in tissue culture

A

activation of telomerase to maintain telomere length.

high activity in at least 90% of cancer and a fraction of precursors/germ cells/stem cells/ some other somatic tissues.

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23
Q

what are telomeres?

A

repetitive sequences TTAGGG at the ends of chromosomes. they form loops to protect chromosome ends. they don’t look like dsDNA breaks and hence prevent end-end fusion

24
Q

theory for replicative senscence

A

telomere hypothesis.
telomerase RNA binds the overhanging 3’ end. telmoerase uses it to elongate the bound DNA (reverse transcriptase) by one repeat unit, the lagging strand s elongated by primase and polymerase, then the telomerase RNA is removed.

25
Q

the role of replicative senescence in stem cells, transit amplifying cells, and differentiated cells.

A
  • stem cells express it.
  • transit amplifying progenitors have a programmed decline in replicative activity due to lack of telomerase.
  • replicative senescence is one of the strict controls that minimises the chances of a cell escaping antiproliferative mechanisms.
26
Q

who does retinoblastoma typically affect?

A

its a rare childhood cancer. peak incidence at 3-4 years old. can be inherited or sporadic.

27
Q

what happens in retinoblastoma

A

both alleles of RB1 mutated. causing loss of the wt RB1 gene product. the tumour cells show loss of heterozygosity.
wt = wild type

28
Q

inherited RB?

A

either pre/pre or pre/post zygotic mutation

29
Q

sporadic RB?

A

both post zygotic mutations

30
Q

somatic cell in individuals who inherit a familial cancer

A

heterozygous in all somatic cells. wt/mut

tumour cells = mut/mut

31
Q

gene and function in retinoblastoma

A

RB1 - cell cycle checkpoint control

32
Q

gene and function in familial adenomatous polyposis coli

A

APC - signal transduction

33
Q

gene and function in Li fraumeni

A

p53 - cell cycle control/DNA damage

34
Q

gene and function in hereditary non polyposis colon cancer/ lynch

A

MLH1,MSH2 - DNA mismatch repair

35
Q

gene and function in familial breast and ovarian cancer

A

BRCA-1 and BRCA-2 , DNA repair, ds break

36
Q

gene and function in basal cell naevus

A

ptch - signal transduction

37
Q

whats a proband?

A

the affected individual

38
Q

gene and function in ataxia telangiectasia

A

AT - checkpoint control/DNA repair

inherit 2 mutant alleles

39
Q

gene and function in blooms syndrome

A

BI - DNA helicase

inherit 2 mutant alleles

40
Q

gene and function in fanconi’s anaemia

A

FA - DNA repair

mut/mut inheritance

41
Q

gene and function in xeroderma pigmentosa

A

XP - DNA excision repair

mut/mut inheritance.

42
Q

what does study of familial cancer tell us

A

1 - it is genetic
2 - more than one mutation is necessary for progression
3 - maintaining error free DNA is crucial
4 - controls restricting cellular lifespan must be overcome for tumour progression
5 - cancer is a multistage process

43
Q

what are oncogenes

A

alleles which if mutated act in a gain-of-function action.

  • mut usually only one allele.
  • usually normal genes important in growht control
44
Q

how do viral oncogenes cause cancer

A

normal cellular growth genes become inappropriately expressed under the powerful action of viral promoters

45
Q

5 mechanisms of activating oncogenes

A 
1 - retrovirus insertion
2 - retrovirus promoter insertion
3 - point mutation
4 - oncogene amplification or truncation
5 - inappropriate regulation of expression
46
Q

give an example of retrovirus encoded oncogene

A

rous sarcoma virus in chickens. Src

47
Q

give an example of retrovirus promoter insertion

A

integration of provirus into a LTR beside a proto-oncogene and hence its expression under the control of viral promoters or enhancers.
= insertional mutagenesis.
seen in a leukaemia of chickens where c-myc is overexpressed

48
Q

give an example of an oncogene activated by point mutation

A

RAS
point mutation at codon 12 or 13 so that it cannot hydrolyse GTP so permanently on.
K-ras protooncogene

49
Q

family members of RAS

A

K-ras, H-ras, N-ras

50
Q

give an example of an oncogene activated by amplification or truncation

A

EGF-R

squamous cell carcinoma - amplified to 100s of copies. or extracellular domain is truncated to constitutively activate.

51
Q

HER2 is a member of which family

A

EGF-R family. amplified in many breast cancers and can be treated with hercetpin which blocks its ligand

52
Q

neuroblastoma amplified gene?

A

N-myc oncogene.
paediatric tumour.
degree of amplification is proportional to the aggressiveness of the tumour.
by deletion of the regulatory sequences for the promoter or use of an inappropriate promoter

53
Q

4 functions of oncogenes

A

1 - growth factors - sis (simian sarcoma virus) platelet derived growth factor
2 - receptors - erbB (avian erythroblastosis virus) EGF-R
3 - signalling proteins - abl (abelson mouse leukaemia virus) tyrosine kinase, or ras (rat sarcoma virus) GTP-neucleotide binding molecular switch
4 - transcription factors - myc (myelocytomatosis virus) binds DNA stimulates proliferation and regulates apoptosis

54
Q

describe tumour suppressor genes

A

1 - alleles which must be inactivated.
2 - both must be mutated, suppressed or lost. ‘recessive’
3 - they are critical control and regulatory genes many of which restrain cell proliferation.

55
Q

summary of oncogenesis

A

1 - its a multistep process
2 - lesions preceding cancer can be identified by morphological changes
3 - these changes reflect the molecular changes that are mutations in genes controlling proliferation, DNA integrity and cell death.

gene mutations can be gain of funciton in proto-oncogenes or loss of function in tumour suppressor genes.

Pathology (38 decks)

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