Chromosomes in Cancer

Question 1

G banded chromosomes are seen in:

Answer 1

Cells arrested in M phase so the chromosome is condensed. Then stained with Giemsa which shows characteristic banding to distinguish chromosomes (size and centromere position)

Question 2

What is comparative genome hybridisation?

Answer 2

When all normal DNA is stained one colour and all tumour DNA is stained another colour and then DNA is hybridised together. The balance of colours determines the amplification of tumour DNA. If there are deletions then the tumour sequences will be less.

Question 3

Karyotype:

Answer 3

Total number of chromosomes in the cell

Question 4

Aneuploidy

Answer 4

Duplication of a particular chromosome i.e. trisomy 21

Question 5

eupliody

Answer 5

duplication of an entire set of chromosomes ie. 3n or 4n

Question 6

Nomenclature for AML

Answer 6

Acute myeloid leukaemia 47, XX, +8

Question 7

Single chromosome relocation includes:

Answer 7

Deletion of part of a chromosome
Duplication of part of a chromosome
Paracentric inversion: In one arm of chromosme
Pericentric inversion: between two arms of a chromosome

Question 8

What is a clastogen?

Answer 8

A reagent that breaks chromosomes (asbestos/radiation)

Question 9

What are the primary abnormalities of tumours involved in?

Answer 9

Establishment of tumour and driving intiation

Question 10

What are the secondary abnormalities of tumours involved in?

Answer 10

Once the tumour has developed, cause tumour progression

Question 11

What is cytogenic noise?

Answer 11

Background level f non-consequential aberrations and instability syndromes.

Question 12

What are gatekeepers?

Answer 12

Genes involved in primary abnormalities that when mutated of have abnormal expression, relieves the cells normal control on cell division, death or lifespan promoting outgrowth of cancer cells. - drive the tumour

Question 13

What are caretakers?

Answer 13

Involved in secondary abnormalities, these are genes that cause genome instability and increasing the frequency of gatekeeper genes

Question 14

Proto-oncogenes are… (In terms of how they cause cancer)

Answer 14

Gain of function and have a dominant effect, only one allele has to be mutated in order for a phenotypic change to occur.

Question 15

Tumour suppressor gene… (In terms of cancer causing ability)

Answer 15

Loss of function, has to have both alleles affected in order to change phenotype.

Question 16

TSG’s and PO’s are usually used for:

Answer 16

Cell proliferation, differentiation, programmed cell death and cell mortality.

Question 17

In cancer, TSG’s and PO’s expression can become…?

Answer 17

Over expression of a the normal protein
Alteration of the protein
Protein is inappropriately expressed (wrong cell at wrong time)
Gene expression in suppressed (TSG)

Question 18

An example of a point mutation causing altered protein (in normal amounts is:)

Answer 18

K-ras mutations in colon carcinoma so that the pathway is constitutively switched on

Question 19

What cant be seen at a chromosomal level?

Answer 19

point mutations

Question 20

An example of gene amplification resulting in overexpression of a normal protein?

Answer 20

Trisomy twelve in Chronic lymphoblastic leukaemia. There is a mutation in one allele that activates the oncogene. The mutated chromosome is then duplicated which gives the tumour a growth advantage or allows expansion of the mutant clone in order to progress the tumour. = Chromosome amplification

Question 21

What is an isochromosome?

Answer 21

When one arm of the chromosome is deleted (i.e. p arm) and the other arm (i.e. q arm) replicates to replace it, forming an isochromosome. In this case, q may be tumourigenic and p may be detrimental to the tumour.

Question 22

What is an example of amplification being a useful diagnostic tool for cancers?

Answer 22

In MYCN in neuroblastomas on chromosome 2. (NB is a common childhood cancer). In oncogensis, MYCN initially amplifies as double minutes before reinserting into the linear DNA. This mass amplificaion can be picked up by a MYCN probe.

Question 23

What type of repeat polymorphisms are unstable?

Answer 23

Minisatellites

Question 24

Slippage of repeats can change what?

Answer 24

The reading frame

Question 25

Double minutes are:

Answer 25

Small fragments of extra chromosomal DNA that are observed in a large number of human tumours including; breast, lung, ovary, colon and neurob. They are a sign of gene amplification and give the cells selective advantages for growth and survival. They frequently harbour amplified oncogenes and genes holding drug resistance.

Question 26

Double minutes are composed of:

Answer 26

chromatin and replicate in the nucleus during cell division. Unlike typical chromosomes, they are composed of circular fragments of DNA, up to only a few million base pairs in size and contain no centromere or telomere.

Question 27

TSG inactivation can occur by (if one allele is already mutated)

Answer 27

1. Deletion of the normal allele in the second chromosome
2. Whole chromosome loss (of chrome containing normal allele)
3. Mutation in the second allele

Question 28

How can you see p53 deletions within the cell?

Answer 28

Hybridise p53 probes in cancer cells. (FISH)

Question 29

Chromosomal abnormalities in haematopoietic tumours:

Answer 29

Rearrangements involving only a few abnormal chromes in an otherwise diploid karyotype. They have many dividing cells.

Question 30

Chromosome abnormalities in solid tumours:

Answer 30

Complex and gross aneuplidy, few dividing cells, making preparations more difficult as harder to get M phase isolation.

Question 31

Burkitts lymphoma involves

Answer 31

t(8;14) c-myc and IgH reciprocal balance translocation, this leads to constitutive activation of c-myc due to high constitutive expression of the Ig enhancer which leads to the cell being unable to exit the cell cycle = tumour formation

Question 32

What is the most common BL translocation and the least common?

Answer 32

Most: t(8;14)(q24, q32)
Least: t(8;22)(q24, q11) and t(2;8)(p12, q24)

Question 33

Follicular lymphoma involves:

Answer 33

t(14;18)(q31;q21) The entire coding sequence of bcl-2 is translocated to the IgH locus. The same protein is produced. Bcl-2 s an antiapoptosis protein so cell survival is increased, there is no increased proliferaiton. Bcl-2 often cooperated with c-myc in tumours, incl. late stage folliclar lymphoma.

Question 34

Chronic Myeloid Leukaemia facts:

Answer 34

Clonal bone marrow disease thought to affect pleuripotent SCs so all haematopoietic lineages are affected. ¼ of all leukaemia cases in the Western world. CML was the first malignancy to be linked to clear genetic abnormality - Philadelphia chromosome

Question 35

CML chromosomal abnormalities:

Answer 35

t(9;22)(q34, q11) This is the translocation in -90% of all cases. The c-abl gene is translocated to the breakpoint cluster region of C22. The first exon of c-abl remains in C9 and the protein fuses with the first or second exon of bcr. c-abl has tyrosine kinase activity and in the fusion protein, this is greatly increased it is responsible for the majority of the transforming effects.

Question 36

How big is the bcr-abl fusion protein?

Answer 36

Varies dependent on where the breakpoint on bcr is (where the fusion occurs)

Question 37

the hybrid bcr-abl leads to:

Answer 37

Decrease/no DNA repair, Increase cell cycling and tumourigenesis.

Question 38

What drug inhibits bcr-abl and how?

Answer 38

Gleevec binds to the TK active site of the BCR able, preventing substrates from entering the kinase domain and being phosphorylated. Therefore the tumour cell cannot proliferate.

Question 39

In solid tumours how many mutation events are required for malignancy and what does this mean chromosomally?

Answer 39

6-8 and high levels of aneuploidy.

Question 40

Rb protein has what deletion:

Answer 40

del(13)(q14)

Question 41

NF-1 has what deletion:

Answer 41

del(1)(p31p36)

Question 42

WT-1 has what deletion?

Answer 42

del(11)(p13)

Question 43

Why is it difficult to identify the cancer related genes in recurrent abnormalities?

Answer 43

Because the aberrations often contain multiple genes more than one of which may be important.

Question 44

What translocation is present in around 50% of prostate cancers?

Answer 44

A translocation that involves an androgen refuted protease

Question 45

Chromothripsis is:

Answer 45

In 25% of bone cancers and 2-3% of all other cancers and is local firestorms of chromosomal rearrangements (bits of chromosome explode and are randomly rejoined back together.)

Question 46

Chromosomal instability or CIN is:

Answer 46

Change in chromosome number without altering structure - seen in 85% of carcinoma (aneuploidy)

Question 47

CIN causes:

Answer 47

general chaos that progressively envelops cancer cells as they advance towards highly malignant states. Cancers scramble their genomes to promote neoplastic growth.

Question 48

Non-displacement is:

Answer 48

When sister chromatids usually separate in M phase there is a checkpoint that ensures they separate correctly. If this fails both sister chromatids go to one pole and the daughter cell will have an extra chromosome

Question 49

When chromosomes fail to attach to the mitotic spindle it is called? and causes?

Answer 49

non-disjunction and causes loss of chromosomes to one daughter cell.

Question 50

Merotely is when:

Answer 50

Kinetochores attach inappropriately to opposing sets of spindle fibres s that the chromatid becomes stranded in the middle of the cell (should be able to draw diagram of this)

Question 51

What are cancer cells more tolerant of and what does it lead to:

Answer 51

merotely and this leads to anueploidy.

Question 52

What ttends to happen to centrosomes in cancer?

Answer 52

There are multiple centrosomes rather than just one. Multiple centrosomes results in triradial or quadraradial mitotic spindle array. (Can be introuced by oncogenic factors)

Question 53

Blooms syndrome:

Answer 53

Multiple occurrences of cancer, first on by 25, diagnosis by the highly elevated spont sister chromatid exchange rate. (high cross ver rate)

Question 54

Hereditary breast cancer:

Answer 54

BRCA1 & 2 encode proteins that don’t look like each other or any other cellular proteins, they are not mutated in sporadic breast cancer and are involved in DNA repair.

Question 55

Cytogenetics:

Answer 55

study of structure and function of chromosomes