precursors, carcinogenesis...

Question 1

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

Answer 1

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

Question 2

cytology of intraepithelial neoplasms.

Answer 2

• abnormal nuclei
• abnormal mitosis,
• loss of nuclear polarity
• loss of differentiation.

Question 3

why are pre-cancerous changes imp?

Answer 3

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

Question 4

pre cancerous changes in breast tissue?

Answer 4

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.

Question 5

how many women are affected by breast cancer in developed countries

Answer 5

about 1 in 11

Question 6

adenocarcinoma incidence

Answer 6

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.

Question 7

describe large intestine adenomas

Answer 7

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

Question 8

importance of large intestine adenomas?

Answer 8

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.

Question 9

what are carcinogens/oncogens?

Answer 9

agents which induce cancer

Question 10

what is carcinogenesis/oncogenesis?

Answer 10

the process of cancer induction

Question 11

what are the classes of carcinogen

Answer 11

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

Question 12

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

Answer 12

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

Question 13

2 potent carcinogens in tar

Answer 13

3-benzpyrene

3’methylcholanthene

Question 14

5 principles of carcinogenic action

Answer 14

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)

Question 15

2 stages of carcinogenesis

Answer 15

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.

Question 16

what is progression in carcinogenesis?

Answer 16

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

Question 17

what is cell transformation

Answer 17

the change in phenotype and behaviour of a cell.

Question 18

what is replicative senscence

Answer 18

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

Question 19

what the hayflick number

Answer 19

the number of divisions a cell can undergo before apoptosis.

Question 20

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

Answer 20

very rarely undergo spontaneous immortalisation in tissue culture

Question 21

name some viral oncogenes that can cause immortalisation.

Answer 21

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

Question 22

what is the cause of immortalisation in tissue culture

Answer 22

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.

Question 23

what are telomeres?

Answer 23

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

Question 24

theory for replicative senscence

Answer 24

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.

Question 25

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

Answer 25

- 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.

Question 26

who does retinoblastoma typically affect?

Answer 26

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

Question 27

what happens in retinoblastoma

Answer 27

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

Question 28

inherited RB?

Answer 28

either pre/pre or pre/post zygotic mutation

Question 29

sporadic RB?

Answer 29

both post zygotic mutations

Question 30

somatic cell in individuals who inherit a familial cancer

Answer 30

heterozygous in all somatic cells. wt/mut | tumour cells = mut/mut

Question 31

gene and function in retinoblastoma

Answer 31

RB1 - cell cycle checkpoint control

Question 32

gene and function in familial adenomatous polyposis coli

Answer 32

APC - signal transduction

Question 33

gene and function in Li fraumeni

Answer 33

p53 - cell cycle control/DNA damage

Question 34

gene and function in hereditary non polyposis colon cancer/ lynch

Answer 34

MLH1,MSH2 - DNA mismatch repair

Question 35

gene and function in familial breast and ovarian cancer

Answer 35

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

Question 36

gene and function in basal cell naevus

Answer 36

ptch - signal transduction

Question 37

whats a proband?

Answer 37

the affected individual

Question 38

gene and function in ataxia telangiectasia

Answer 38

AT - checkpoint control/DNA repair | inherit 2 mutant alleles

Question 39

gene and function in blooms syndrome

Answer 39

BI - DNA helicase | inherit 2 mutant alleles

Question 40

gene and function in fanconi's anaemia

Answer 40

FA - DNA repair | mut/mut inheritance

Question 41

gene and function in xeroderma pigmentosa

Answer 41

XP - DNA excision repair | mut/mut inheritance.

Question 42

what does study of familial cancer tell us

Answer 42

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

Question 43

what are oncogenes

Answer 43

alleles which if mutated act in a gain-of-function action. - mut usually only one allele. - usually normal genes important in growht control

Question 44

how do viral oncogenes cause cancer

Answer 44

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

Question 45

5 mechanisms of activating oncogenes

Answer 45

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

Question 46

give an example of retrovirus encoded oncogene

Answer 46

rous sarcoma virus in chickens. Src

Question 47

give an example of retrovirus promoter insertion

Answer 47

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

Question 48

give an example of an oncogene activated by point mutation

Answer 48

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

Question 49

family members of RAS

Answer 49

K-ras, H-ras, N-ras

Question 50

give an example of an oncogene activated by amplification or truncation

Answer 50

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

Question 51

HER2 is a member of which family

Answer 51

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

Question 52

neuroblastoma amplified gene?

Answer 52

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

Question 53

4 functions of oncogenes

Answer 53

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

Question 54

describe tumour suppressor genes

Answer 54

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.

Question 55

summary of oncogenesis

Answer 55

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.