1.09 - Cancer Genetics

Question 1

What are the stages of the cell cycle and what occurs in each?

Answer 1

G1: Cellular contents, excluding the chromosomes are duplicated.
S: Each of the 46 chromosomes is duplicated by the cell
G2: The cell “double checks” the duplicated chromosomes for error and makes any needed repairs
Mitosis: Cellular division

Question 2

What is the purpose of Check Points in the cell cycle?

Answer 2

They are there to ensure that chromosomes are intact and that critical stages of the cell cycle are complete before progressing to the next staged.
Defects in genes which control the cel cycle may cause cancer

Question 3

Define: Proto-oncogene

Answer 3

A normal gene that can undergo mutation to become an oncogene, a gene that has the ability to induce cancer

Question 4

Define: Oncogene

Answer 4

A gene that has the potential to cause cancer

Question 5

Define: Tumour Suppressor Gene

Answer 5

A gene that protects a cell from one step on the path to cancer

Question 6

Define: Apoptosis

Answer 6

Programmed cell death required for development and normal cell termination

Question 7

Define: Apoptotic genes

Answer 7

Genes that promote apoptosis

Question 8

Define: Anti-apoptotic genes

Answer 8

Genes that inhibit apoptosis

Question 9

What are the two broad categories for mutations that can lead to cancer?

Answer 9

Inherited and Acquired (somatic)

Question 10

Describe Inherited Gene Mutations as they relate to cancer

Answer 10

These mutations are passed from parent to child throughout the egg or sperm. These mutations are therefore in every cell in the body. As all cells already have one mutation, they only need to acquire a mutation in the other gene for cancer to present

Question 11

Describe Acquired (somatic) mutations as they relate to cancer

Answer 11

No mutations present in the egg or sperm. These mutations are acquired at some point in the person’s life. This type of mutation occurs in one cell and then is passed on to any new cells that are offspring of that cell. The person starts with two normal genes –> need to acquire mutations in both genes for the cancer to present

Question 12

Describe the Two-Hit Theory For Cancer Causation

Answer 12

•Non-Hereditary: All cells start as normal cells, with two normally functioning genes. Through a rare event they acquire a mutation in one of those genes (one-hit cell). After another rare event the cells acquires a second mutation in the other gene (two-hit cell). This two hit cell will then lead to cancer development
•Hereditary: There are no normal cells, as all cells start with the mutation from conception (all cells start as a one-hit cell). This cell then only needs to acquire a mutation in the second gene to become a two-hit cell and produce cancer.
Cells require ‘Two-Hits’ in the gene for the cancer to present.

Question 13

Describe Retinoblastoma

Answer 13

Caused by a mutation in a really important tumour suppressor gene (retinoblastoma 1) –> uncontrolled cellular division of a retinoblast cell (retinal progenitor cell).
40% of cases are hereditary, 60% have no family history.

Question 14

Compare and Contrast Hereditary & Sporadic Retinoblastoma

Answer 14

• Non-Hereditary: All cells start as normal cells, with two normally functioning genes. Through a rare event they acquire a mutation in one of those genes (one-hit cell). After another rare event the cells acquires a second mutation in the other gene (two-hit cell). This two hit cell will then lead to cancer development
• Hereditary: There are no normal cells, as all cells start with the mutation from conception (all cells start as a one-hit cell). This cell then only needs to acquire a mutation in the second gene to become a two-hit cell and produce cancer.

Question 15

Describe Loss of Heterozygosity

Answer 15

Is a gross chromosomal event that results in the loss of the entire gene and the surrounding chromosomal region. Leads to many cancers.

Question 16

Describe the three different avenues for Loss of Heterozygosity

Answer 16

Somatic Recombination: Gene becomes mutated –> Part of mutated chromosome gets copied and replaces the respective part on the normal homologous chromosome
Loss and duplication: Gene becomes mutated, non-dysjunction during cell division results in nucleus with one normal chromosome and two mutated chromosomes. Random elimination of the normal chromosome will leave cell with two mutated chromosomes.
Chromosome Loss: Gene becomes mutated and normal chromosome is lost –> leaving the cell with only one mutated copy of the chromosome

Question 17

Describe the mechanism of Retinoblastoma 1 in the development of Retinoblastoma.

Answer 17

Under normal condition RB1 blocks E2f-DP complex and halts cell proliferation by inhibiting DNA synthesis
Under pathological conditions, RB1 becomes inactivated or phosphorylated and is unable to inhibit DNA synthesis leading to uncontrolled initiation of DNA synthesis and cel proliferation.
Gene function can be lost through either mutation, loss of heterozygosity or as a result of other control factors (cyclin D)

Question 18

Describe P53

Answer 18

“Guardian of the Genome”
Tumour suppressor gene
Somatic mutation of P53 occur in almost every type of cancer at high rates.
Basal levels are relatively low. P53 levels are increased in response to stressors such as DNA damage, oxidative stress, osmotic shock and oncogene dysregulation.
Functions to arrest the cell cycle at G1/S phase, Repair DNA and if need be, initiate apoptosis.

Question 19

Describe how P53 works and is regulated

Answer 19

Under normal conditions P53 promotes expression of MDM2 which in turn negatively regulates P53 through ubiquitin mediated degradation.
When DNA damage occurs (double strand breaks), ATM is recruited, which phosphorylates P53 and prevents the association between P53 and MDM2.
P53 is then able to have its effect in repairing DNA.
However, as the levels of P53 rise due to the phosphorylation, it promotes expression of MDM2 and the levels of P53 return to normal

Question 20

Describe the fate of a cell after DNA damage in the presence and absence of P53

Answer 20

When P53 is working normally, it will either repair the DNA after it is damaged and allow division to proceed, or it will signal for apoptosis and the cell to die.
However, when P53 is mutated and not able to function properly, the damage to the DNA can either lead to a failure in mitosis and subsequent cell death, or cell division can continue as normal and one or both cells will have acquired this new mutation and possibly lead to a tumour.

Question 21

Describe Chronic Myelogenous Leukaemia

Answer 21

Rare cancer with rapid and uncontrollable increase in white blood cells numbers. Caused by a chromosomal mutation in the proto-oncogene ABL1, making it an oncogene.

Question 22

Describe the chromosomal mutation that occurs in Chronic Myelogenous Leukaemia and how it leads to cancer

Answer 22

Translocation of ABL on chromosome 9 to chromosome 22.
ABL is now controlled by the promotor of BCR (a highly expressed protein) and forms a chimeric BCR-ABL protein. ABL is normally only expressed when it is need but now that it is associated with the promotor of a highly expressed gene, its levels in the cell are significantly increased. This leads to increased cell proliferation without being regulated.

Question 23

Describe BRCA1 and BRCA2

Answer 23

They are both nuclear proteins that act as tumour suppressors. They largely act to repair DNA.
Mutations in these genes, increase the risk of an individual developing breast or ovarian cancer.
Strong genetic component: 10 fold increase in cancer if more than one first degree relative is affected.

Question 24

Describe the mechanism behind how BRCA1 leads to breast and ovarian cancer

Answer 24

BRCA1 associates with a protein called NRF2.
Normally BRCA1 together with NRFS repairs DNA and has anti-oxidant activity.
If BRCA1 becomes mutated, in most cells, this would lead to death of the cell as a result of the increased oxidative stress.
However in breast and ovarian cells, the high amount of oestrogen can partially activate NRF2 in BRCA1 mutated cells, preventing the build up of enough reactive oxygen species and allowing the cell to survive with the BRCA1 mutation.
This means the surviving cells are more susceptible to DNA damage as they would have lost vital repair mechanisms.