Chromosomes In Cancer

Question 0

How many chromosomes are in human germline cells?

Answer 0

23

Question 1

How many chromosomes are in human somatic cells?

Answer 1

46

Question 2

What are the types of single chromosome rearrangements?

Answer 2

Deletions, duplication, inversion.

Question 3

What are the types of double chromosome rearrangements?

Answer 3

Insertions and translocations.

Question 4

How can chromosomal abnormalities contribute to carcinogenesis?

Answer 4

Can be the initiating event in carcinogenesis.
Chromosomal instability in tumours may accelerate tumour progression due to defects in DNA repair and chromosome segregation.

Question 5

What are the types of chromosomal abnormalities in neoplastic cells? What do they do?

Answer 5

Primary abnormalities are involved in establishing the tumour.
Secondary abnormalities may be important in tumour progression.

Question 6

What is cytogenetic noise?

Answer 6

Background level of non-consequential aberrations (random distribution throughout the genome).

Question 7

Describe the cancer susceptibility genes in primary abnormalities.

Answer 7

Genes whose mutation or altered expression relieves the normal controls on cell division, death, or lifespan, promoting the outgrowth of cancer cells. Termed gatekeepers.

Question 8

Describe the cancer susceptibility genes in secondary abnormalities.

Answer 8

Those whose disruption causes genome instability, increasing the frequency of alterations in gatekeeper genes, termed caretakers.

Question 9

What are the mechanisms for oncogene activation?

Answer 9

Point mutation in DNA sequence - altered protein in the normal amount.
Gene amplification - over expression of a normal protein.
Chromosome translocations or rearrangements - man give rise to a new gene product, or may move the oncogene into a transcriptionally active region. In this case the normal protein is produced in excess and is not controlled in the usual way.

Question 10

What is gene amplification?

Answer 10

Duplication of part of a chromosome.

Question 11

What is a minisatellite?

Answer 11

Repeat of 10-60 nucleotides.

Question 12

What is a microsatellite?

Answer 12

Repeat of less than 10 nucleotides. Also known as short tandem repeats.

Question 13

Describe burkitts lymphoma translocation.

Answer 13

C-myc is moved to the Ig H locus on chromosome 14, resulting in enhanced c-myc protein production. Cells are prevented from leaving the cell cycle resulting in uncontrolled cell proliferation.

Question 14

What translocation is commonly used to detect Follicular Lymphoma?

Answer 14

T(14;18)

Question 15

What are the consequences of t(14;18)(q32;q21)?

Answer 15

The entire coding sequence of bel-2 is translocated.
The protein produced is the same.
High level of bcl-2 protein expression.
Bcl-2 protein protects the cell against apoptosis leading to increased cell survival.
Bcl-2 does not increase cell proliferation.
Bcl-2 cooperates with c-myc in many tumours, including late stage follicular lymphoma.

Question 16

What is chronic myeloid leukaemia?

Answer 16

Clonal bone marrow disease.
Abnormality thought to occur at the level of the pluripotent stem cell, therefore all haematopoietic lineages are involved.
Caused by chromosomal translocation between 9 and 22, Philadelphia chromosome.

Question 17

What is the bcr-abl fusion gene?

Answer 17

The proto-oncogene c-abl is moved from 9q34 to the breakpoint cluster region on chromosome 22q.
The first exon of c-abl remains on chromosome 9, whilst the first and second exons of the bcr gene are fused to the remainder of the c-abl gene.
This gene produces a new protein, it does not amplify an existing protein. Promotes tumour growth.

Question 18

What are the biological effects of Bcr-Abl?

Answer 18

Drives cells towards tumorigenesis by increasing the cell cycle and inhibiting DNA repair.

Question 19

Define aneuploid.

Answer 19

Multiple abnormalities, so it is difficult to determine which is the most relevant for tumour formation and growth.

Question 20

What is chromothripsis?

Answer 20

Bits of the chromosome explode, DNA repair mechanisms try to put them back together.

Question 21

Describe the involvement of chromosomal instability (CIN) in cancer.

Answer 21

General chaos progressively envelopes cancer cells as they advance towards highly malignant states.
Casual importance: required for tumours to scramble their genomes to arrive at chromosomal configurations that are more favourable to neoplastic growth.

Question 22

What is usually the cause of chromosomal instability?

Answer 22

Mis-segregation of chromosomes during mitosis.
When sister chromatids separate in M phase there is a checkpoint that ensures they separate correctly. If this fails and both sister chromatids go to one pole, the daughter cell will have an extra chromosome (non-disjuction).

Question 23

How does merotely occur?

Answer 23

Inappropriate connection of kinetochore complexes to microtubules.
Microtubules attach from both sides, the chromosome becomes stuck in the centre of the cell.
Cancer cells are particularly tolerant to this abnormality.

Question 24

Describe the formation of multipolar mitotic apparatus.

Answer 24

Incorrect formation of spindles results in the formation of multiple centrosomes, leading to a triradial mitotic spindle array.

Question 25

What are genetic instability syndromes?

Answer 25

Defects in DNA repair such as Bloom’s syndrome.

Question 26

Describe the process of non-homologous end joining in DNASE repair.

Answer 26

Religation of broken ends. Efficient but prone to error. May stick together the wrong ends.

1. Double-strand break.
2. Resection of single strands by exonuclease.
3. DNA strands brought together, possible limited base pairing between them.
4. Strands filled in, joined by ligation.
5. Double helix reconstruction.
6. Several base pairs present in the original wild type sequence are missing.

Question 27

Describe the process of homologous recombination.

Answer 27

Complex, ensures no information is lost. Uses undamaged version of chromosome as a template.

1. DsDNA break.
2. Resection by exonuclease.
3. Base pairing with unwound DNA of sister chromatid.
4. Strand extension.
5. Disengage and repair.
6. Fill in the gaps, restore to wild type.

Question 28

Why are translocations common in leukaemias and lymphomas?

Answer 28

The misrepair of chromosome damage during the rearrangement of the T cell receptor or immunoglobulin genes.