Lecture 26

Question 1

What causes cancer?

Answer 1

Genetic instability which leads to mutations within the cells

Question 2

Where can mutations come from?

Answer 2

• can be inherited by a daughter cell

- additional mutations can occur

Question 3

How does gene expression occur?

Answer 3

This process is highly regulated and controlled

• the DNA undergoes transcription before the introns are spliced out of the primary transcript (RNA)
• The mature transcript (mRNA) undergoes protein synthesis/translation

Question 4

What can population genetics be used for?

Answer 4

It can be used to identify mutation carriers among parents and offspring

Question 5

What is the two-hit model?

Answer 5

For cancer to form, it has to under go at least two mutations

• oncogene mutations have to be gain of function
• tumour suppressor gene mutations have to be homozygous and loss of function
• a single mutation in either of these genes could cause a benign tumour

Question 6

Why is more than one mutations necessary to cause cancer?

Answer 6

• Cells build up a large amount of redundancy with DNA repair, etc.
• Multiple mutations requires repairs in multiple ways
• The mutations have to be in genes with critical functions (ie., p53)

Question 7

What is the mutation frequency like across cancers?

Answer 7

• the frequency of somatic mutations is all over zero

- each of the shown cancers had more than one mutation in their bases (C to T, C to A, etc.)

Question 8

What are germline (hereditary) mutations?

Answer 8

• Inherited mutation is presented in egg or sperm
• All cells carry the mutation (entire organism)
• Usually autosomal dominant transmission
• 1st degree family members of carriers are at 50% risk
• Incomplete penetrance

Question 9

What are Familial mutations?

Answer 9

• Inherited within a family of a specific cancer more than the expected frequency
• no specific pattern of inheritance

Question 10

What are sporadic (somatic) mutations?

Answer 10

• Non-hereditary causes (not picked up from mom and dad)
• No pattern of inheritance
• Genetic susceptibility test usually do not reveal mutation
• Not present in zygote
• Acquired in one cell and passed onto daughter cells
• Not passed onto off-spring
• Much more common in cancer

Question 11

What is “Sporadic” Cancer?

Answer 11

• Onset later in life
• No clear pattern on onside of family
• although family members may have a small increased risk due to similar environments and lifestyles
• No inherited gene mutation

Question 12

How does hereditary retinoblastoma form?

Answer 12

Germline mutation

1. A sperm cell has the RB mutation which results in the fertilized egg having a 50% chance of inheriting it
2. Mutation in one copy of RB gene is inherited in all body cells
3. Mutation in second copy of RB gene occurs in one or more retina cells

Question 13

How does nonhereditary retinoblastoma occur?

Answer 13

Somatic mutation

1. Fertilized egg inherits no RB mutation
2. Mutation in one copy of RB gene occasionally occurs as cells divide
3. Mutation in second copy of RB gene occurs in one or more retina cells

Question 14

Explain how cancer occur from inherited and sporadic mutations.

Answer 14

Every cell including every ovary cell has the inherited mutation. Sporadic gene mutations occur. Overtime, key gene mutations may add to the inherited mutation and lead to tumor growth and cancer (accumulation of mutations).

Question 15

What percentage of breast and ovarian cancer is hereditary?

Answer 15

Breast: 5-10%
Ovarian: 5-10%
Both are mostly caused by sporadic mutations

Question 16

Are mutations within cancers similar?

Answer 16

No, the mutational landscape is spatially different and there is, at most, less than 10% of similarities between mutations

Question 17

What is significant about the common hereditary genes in cancer?

Answer 17

• There is more than one mutation in each of the hereditary genes in all cancers
• p53 appeared to be mutated in all cancers

Question 18

Why is BRCA significant in the topic of cancer?

Answer 18

BRCA mutations increase the risk of breast and ovarian cancer
- it increases the risk as the patient ages

Question 19

What is BRCA?

Answer 19

• BReast CAncer susceptibility gene; orthologs in other mammalian species
• involved in normal dsDNA break repair and homologous recombination
• it’s a tumour suppressor gene
• Classic inherited mutation and also somatic

Question 20

If there has been history of breast or ovarian cancer in your patient and they’re high risk, what would you initially suggest they do?

Answer 20

You would refer them to a specialized Hereditary Breast and Ovarian Cancer (HBOC) clinic. They would undergo Germline BRCA testing which results in informed decision-making to decide of form of prevention treatment.

Question 21

In a BRCA1/2 mutation carrier, what happens if a normal cell, with a functioning BRCA1/2, undergoes a single strand break and is then treated with PARP inhibitor.

Answer 21

The single strand break becomes a double strand break, because BRCA is active, it is able to repair the break and the cell survives.

Question 22

In a BRCA1/2 mutation carrier, what happens if a tumour cell, with a functioning BRCA1/2, undergoes a single strand break and is then treated with PARP inhibitor.

Answer 22

Once the cell undergoes a double strand break, the BRCA repairs the break resulting in a resistant tumour cell

Question 23

In a BRCA1/2 mutation carrier, what happens if a tumour cell, with a non-functioning BRCA1/2 due to LOH, undergoes a single strand break and is then treated with PARP inhibitor.

Answer 23

Once the double strand break occurs, the cell becomes synthetically lethal due to the non-functioning BRCA. This results in a sensitive tumour cell.

Question 24

How have labs discovered targets?

Answer 24

By large-scale genomic screens for synthetic lethality.

• WT and mutant Ras cells are plated on a 96-well microtitre plate
• An shRNA or siRNA library is introduced to cause the silencing of genes
• Cell growth is monitored
• If there is no growth in the same spots on both plates -> common lethal, knockdown of essential genes
• If there is no growth on a unique spot on the Ras mutant plate -> synthetically lethal, knockdown of unique genes (synthetically lethal genes)

Question 25

Why are RAS mutations common in cancers?

Answer 25

``` Regulates many processes in the cell The mutation effects: - Parallel survival signals - Altered transcriptional programme - Chromosomal stability - Suppression of senescence and apoptosis ```