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Flashcards in Carcinogenesis 2 Deck (62):
1

define darwinian evolution and clonal expansion of the intent mutant

clonal expansion of the initiating mutant, in order that it will acquires 2nd mutation.

2

define caretaker gene

maintain genetic stability by repairing damaged DNA and replication errors and controlling the accuracy of mitosis.

3

what feature of tumour cells can mutation in a caretaker gene cause

genetic instability.

4

what type of genes are caretaker and gate keeper genes

tumour suppressor genes

5

define gatekeeper gene

negative regulators of the cell cycle and proliferation.
positive regulators of apoptosis.
positive regulators of cell differentiation.

6

do both tumour suppressor genes have to be hit in order for inactivation

Yes.

7

how can the promoter region of tumour suppressor genes be inactivated

hypermethylation of the CpG islands.

8

define epigentic silencing

hypermethylation of the CpG islands (promoter region)

9

what is typically the cause of the 1st hit in tumour suppressor genes

single point mutation.

10

what is typically the cause of the 2nd hit in tumour suppressor genes

chromosomal non-disjunction (leads to aneuploidy)

Chromosomal recombination- takes place in meiosis as it combines maternal and paternal genetic material. However in somatic cells during mitosis it can create a daughter cell that is homozygous for the first mutation in TSG.

11

what is the most common feature of tumour cells

aneuploidy- daughter cells have the wrong amount go chromosomes.

12

how do familial cancers predispose individuals with a greater risk of developing a cancer

inheritance of a mutant copy of a gatekeeper or caretaker gene, so only require 1 hit to be classes as cancer.

13

what gene is involved in retinoblastoma and is it a gate keeper of caretaker

gatekeeper
RB1

14

what gene is involved in Li- Fraumeni and is it a gate keeper of caretaker

p53
gate keeper and care taker

15

what are the principal tumours in Li fraumeni

sarcomas and breast

16

what gene is involved in familial adenomatous polyposis and is it a gate keeper of caretaker

APC
Gate keeper

17

what are the principal tumours in familial adenomatous polyposis

colorectal

18

what gene is involved in familial breast cancer and is it a gate keeper of caretaker

BRAC1/BRAC2
caretaker

19

what are the principal tumours in familial breast cancer

breast and ovarian

20

what gene is involved in hereditary non polyposis colorectal cancer and is it a gate keeper of caretaker

hMLH1, hMSH2
care taker

21

what are the principal tumours in hereditary non polyposis colorectal cancer

colon endometerial

22

define proto-oncogenes

promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis

23

define oncogenes

mutations lead to activated versions or increased expression of proto-oncogenes – GAIN OF FUNCTION

24

how many mutant oncogene do you need to induce gain of function

one- the mutated gene is dominant.

25

what mechanisms activate oncogenes.

Translocation of a proto-oncogene from a low transcriptionally active site to an active site - aberrant expression of the oncogene.
E.g. moving the gene to where immunoglobulin’s are present as they are expressed transcpitionally a lot.
Point mutation - substitution of a single base pair can alter an amino acid in the protein causing it to become hyperactive
Amplification by insertion of multiple copies of an oncogene – increased expression.

26

what is the minimum number of genetic alternations required to transform a normal cell into a neoplastic cell

3

27

stage by stage tumorigenesis of colorectal cancer.

normal epithelium- loss of APC
Hyperplastic epithelium- DNA hypomethylation.
early (activation of K ras)- intermediate(loss of 18q TSG) - late adenomas
loss of p53- carcinoma
invasion and metastases.

28

do tumour cells require a stimulus of positive growth factor before they enter the cell cycle and divide

NO

29

define signal transduction (process used to inform cells whether they need to enter the cell cycle )

passage of signals from outside the cell, through the almost impervious cell membrane, across the cytoplasm and into the nucleus, where changes in gene expression can take place

30

what factors carries signals about whether a cell needs to enter the cell cycle or not

growth factor

31

where are growth factor receptors located

on the cell membrane of cells.

32

what is the function of growth factor receptors

stimulate a cascade of signalling events that culminate in the nucleus with changes in gene expression.

33

how do oncogenes manipulate RAS in order to continue cell division and proliferation

cancer cells carry an activated RAS oncogene mutation where they alter 1 amino acid involved in the cleaving of the phosphate group from GTP. This means that once the RAS oncoprotein has acquired a GTP molecule and shifted into its active state it is unable to revert back to an inactive state

34

do cancer cells respond to negative growth factors which inform cells to leave the cell cycle

No

35

what is the function of RB protein

key regulator of cell cycle by preventing progression from G1 to S phase.

36

how to tumours prevent responding to negative growth factors

Inactivation of RB gene.

37

in a non proliferating cell what is the function of RB

in a non proliferating cell does the RB bind to and suppress the activity of transcription factors whose function is to switch on genes required for proliferation

38

In a proliferating cell cell what is the function of RB

retinoblastoma protein is phosphorylated, and therefore inactivated, by kinase enzymes that have been switched on via a proliferation signal transduction pathway

39

what negative growth factor activates RB and how does it activate RB

transforming growth factor beta (TGFbeta).

stimulating the expression of proteins that inhibit the kinase enzymes that inactivate RB

40

what enzymes inactivate RB

kinase

41

when RB is phosphrylated is it active or inactive

inactive

42

do tumour cells have a finite replicative ability before they become senesce and die due to loss of telomeres

No

43

how to tumour cells have a infinite replicative ability

Tumour cells express telomerase that replaces the lost material and cells become immortal.

44

what is the function of telomerase

maintain telomere length.

45

what are the telomeres made of

Thousands of repeats of hexanucleotide sequence

46

what is the 6 base composition of the telomere hexanucleotide sequence

TTAGGG

47

due toe a defiecncy in DNA replication process what is lost every time you replicate DNA

part of the telomere.

48

what happens to cells when all the telomere has been lost after numerous replications

chromosomes become exposed and are able to fuse with each other resulting in karyotypic chaos, which usually triggers apoptosis

49

how does telomerase replace lost telomeres

using an RNA template.

50

when is telomerase typically expressed in normal human cells

embryogenesis but expression is lost in cells once they differentiate

51

how do tumour cells resist apoptosis

P53 induces cell cycle arrest to allow repair of DNA damage
But also induces apoptosis if too much damage
TP53 inactivation leading to loss of apoptotic response is the most common genetic abnormality in human tumours

52

what gene is involved in apoptosis

p53

53

what size tumours need a blood supply

>2 mm

54

what is the name of the transcription factor which induces VEGF, and what causes the transcription factor to be stimulated

HIF-1 transcription factor
hypoxia

55

what is the function of VEGF

construct new capillaries and vessels
actively recruit endothelial cells that proceed to construct new capillaries and vessels

56

Can malignant cells invade other tissue and detach from their own

Yes

57

what holds cells together

E cadherin

58

how does e cadherin become inactivated in genes

mutation/hypermethylation of the gene

59

what is epithelial mesenchymal transition

Mesenchymal cells are motile and secrete proteases - allows them to break through basement membrane and invade the underlying stroma

60

what is the clinical application of tumour markers

screening
diagnosis
prognosis
therapy
monitoring

61

example of a tumour marker which is predictive for prognosis.

• Gene expression profiling of acute myeloid leukaemia (AML) subtypes
• AML subtypes with different translocations (t(11q23)/MLL, t(8;21), t(15;17), inv(16), and AML with complex aberrant karyotypes) are clearly distinguished based on differential genomic expression from 749 probe sets

62

example of a tumour marker which is a predicitve marker for therapeutic response.

• HER2 (erbB2/neu) codes for a +ve growth factor receptor
• Overexpression found in ~30% of breast tumours (gene amplification)
• Makes cells more responsive to, or independent of, +ve growth factors
• Herceptin is an antibody drug targeted to HER2 and dampens the effects of an overactive HER2 receptor
• Only patients with HER2 overexpression have Herceptin treatment as individuals without overactive HER2 receptors will have no beneficial effect