Unit 4 - General Concepts of Cancer and Protecting the Genome Flashcards Preview

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Flashcards in Unit 4 - General Concepts of Cancer and Protecting the Genome Deck (73)
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1

cancer - biology vs molecular level

out of control cellular proliferation (bio)

damage to genetic material (mutations and epigenetic) that affect cellular proliferation

2

3 types of mutations in cancer cells

ONCOGENIC

TUMOUR SUPPRESSIVE

NEUTRAL

3

oncogenic mutation

ras

myc

cyclin D

normal growth promoting genes (proto-oncogenes) become either hyperactive or inappropriately active

dominant mutations = mutation of only 1 allele required

4

tumour suppressive mutation

normal growth restraining genes become lost or down-regulated

recessive mutation = mutation of both alleles required (to lose tumour suppressive function)

BRCA1 and 2

TP523

5

neutral mutation

cancer cells have 1000s of mutations to genes that have little or no effect on aetiology of cancer

cancer evolves a mutagenic phenotype

6

protooncogenes when mutated =

driving with foot on the accelerator

7

normal (stem) cells

low instability

no cells have genetic alteration required to overcome the selection barrier

NO TUMOUR

8

increased genetic instability

at least 1 cell contains the requisite genetic alteration to overcome the selection barrier (clonal selection)

barrier traversed and population of mutant cells eventually accumulates the new mutations required to cross the next selection barrier

significant step towards tumourigenesis

9

too much genetic instability

too many mutations accumulate to allow viability

cells die - apoptosis, necrosis

NO TUMOUR

10

6 selection barriers

reduced requirement for growth factors - autocrine stimulation

insensitivity to inhibitory signals

escape from senescence (cellular immortality)

evasion of apoptosis

stimulated angiogenesis

invasion/metastases

11

how are these selection barriers overcome

by inactivating tumour suppressors and activating oncogenes

tumours - hostile cellular environments

e.g. periods of anoxia, malnutrition

fluctuating hormonal influences and immune attack

a fertile breeding ground for mutations

similarly, bacteria with higher levels of genomic instability, but not too high, adapt to and eventually dominate new environments

12

challenge posed by the somatic mutation hypothesis

very low mutation rate - 1 x 10-10 nucleotides/cell/division for human somatic cells

diploid human genome = 6.4 x 109

1016 cell divisions in a human lifetime are insufficient to permit a single cell to obtain the estimated 5-7 advantageous mutations required to produce a cancer

⇒ cancer shouldn't occur with such a low mutation rate

13

the mutator (or genetic instability) hypothesis

cancer cells have significantly elevated (just-right) mutation rates

14

Min tumours

where is there instability

type of karyotype

prevalence

microsatellite instability

instability at the nucleotide level e.g. mutation of MMR results in 10-100 fold increase in mutation

most easily seen at microsatellites

normal karyotype

relatively uncommon e.g. 15% colorectal cancers

15

Cin tumours

where is there instability

karyotype

prevalence

chromosomal instability

instability at chromosomal level

not clear what mutational events initiate Cin tumours - loss of p53, mitotic checkpoints?

abnormal karyotype

most frequent - 85% of colorectal cancers

 

16

similarity between min and cin

NOT FOUND TOGETHER

same oncogenes and tumour suppressors appear to be targeted in both min and cin tumours

17

what is the lifetime risk of many cancers dependent on

the total number of divisions of adult stem cells in the particular tissue rather than on environmental or inherited mutations

the more cell divisions the more likely that random mutation to key cancer driver genes will occur during cell division - 65% of cancer

 

 

18

what explains the extreme variation in cancer incidence across different tissues

> cell divisions ⇒ the more likely that random mutation to key cancer driver genes will occur during cell division

 

19

cancer risk for different tissues

6.9% - lung

1.08% - thyroid

0.6% - brain

0.003% - pelvic bone

0.00072% - laryngeal cartilage

20

proportion of cancers that have an inherited component

5-10% of cancers

21

what effect does exposure to mutagens have

mutagens or viruses cannot account for a 24x variation of lifetime risk throughout alimentary canal

LI - 4.82%

stomach - 8.6%

oesophagus - 0.51%

SI - 0.2% - 3x LESS COMMON than brain tumours even though the brain is protected from environmental mutagens by the BBB

 

22

lifetime risk vs total stem cell divisions

23

tumour

an abnormal uncontrolled growth without physiological function, that can be either benign or malignant

24

benign tumour

confined and not life threatening

25

malignant tumour

invades surrounding tissue and may spread to other parts of the body

26

neoplasia

process of forming tumours (benign or malignant)

27

hyperplasia

small abnormal growth in a part of the body caused by an excessive multiplication of phenotypically normal cells

28

metaplasia

appearance of invading, microscopally normal cells of a type not normally encountered at that site

most frequent at epithelial transition zone e.g. oesophagus/stomach, cervix/uterus

29

dysplasia

small abnormal growth in a part of the body caused by an excessive multiplication of cytologically abnormal (variable size and shape, bigger nuclei, increased mitotic) cells

transitional state between benign and pre-malignant growths

30

transitional state between benign and pre-malignant growths

dysplasia