Cancer in Families and in Individuals

Question 1

What are the normal functions of tumour suppressor genes?

Answer 1

Regulate cell division Regulates apoptosis Regulates DNA Repair
Monitors DNA damage checkpoint TSG is recessive

Question 2

Describe the two hit hypothesis.

Answer 2

It takes two hits (both TSG must be mutated) for a cancer to start The first hit is usually a nonsense. mutation The second hit is usually a larger deletion that removes the other allele and hence the function of the gene completely

Question 3

What is ‘haploinsufficiency’?

Answer 3

The idea that it only takes one hit to give the cell a selective advantage – a 50% decrease in protein is sufficient to give the cell a selective advantage

Question 4

What is a common manifestation of the second hit?

Answer 4

Loss of heterozygosity – the deletion could remove OTHER genes (not use the tumour suppressing gene) that are part of a heterozygous pair
This means that that gene then appears homozygous as one of the alleles has been los

Question 5

What genes predispose to breast and ovarian cancer and what is the lifetime risk?

Answer 5

BRCA1 and BRCA2

60%

Question 6

Describe the patho-genetic mechanism of BRCA genes.

Answer 6

BRCA are tumour suppressing genes (DNA repair genes)
When these DNA repair genes are mutated the DNA repair proteins are impaired leading to dysfunctional DNA repair proteins which causes many further mutations

Question 7

What are two diseases that predispose to colorectal cancer and what are the relative risks?

Answer 7

Familial Adenomatous Polyposis – nearly 100%

Hereditary Non-Polyposis Colorectal Cancer (HNPCC) –80%

Question 8

What are ‘cytogenic changes’?

Answer 8

Visible changes in chromosome structure or number

Question 9

Describe, broadly speaking, how translocations can cause cancer.

Answer 9

The translocation could lead to the formation of a new fusion gene that encodes a protein that has oncogenic properties

Question 10

Explain the cause of Chronic Myeloid Leukaemia.

Answer 10

Translocation between chromosome 9 and 22
BCR gene from chromosome 22 and ABL gene from chromosome 9 fuse in the newly formed Philadelphia chromosome.
The BCR-ABL fusion gene encodes BCR-ABL1 tyrosine kinase, which promotes CML

Question 11

What protein does the fusion gene in CML produce?

Answer 11

BCR-ABL1 Tyrosine Kinase

Question 12

Describe, using an example, a targeted therapy for CML.

Answer 12

Imatinib – inhibits the BCR-ABL1 tyrosine kinase

Question 13

What are the three techniques of quantifying the level of CML in order of sensitivity?

Answer 13

Cytogenetic analysis
Fluorescence in situ hybridisation
RT-qPCR (Reverse Transcriptase Quantitative PCR)

Question 14

Give another example of a translocation causing cancer.

Answer 14

Acute Promyelocytic Leukaemia (APML)

Translocation between chromosome 15 and chromosome 17

Question 15

Which two genes are involved in this translocation?Which two genes are involved in this translocation?

Answer 15

Chromosome 15 = PML (Promyelocytic Leukaemia)

Chromosome 17 = RARA (Retinoic Acid Receptor Alpha)

Question 16

How does this translocation cause cancer?

Answer 16

RARA is a receptor that binds to Vitamin A and then binds to DNA and regulates transcription
The translocation and resulting gene fusion changes RARA so that it binds to DNA too strongly
These genes become silenced – the cell proliferates

Question 17

What treatment is available for this cancer and how does it work?

Answer 17

All Trans Retinoic Acid (ATRA)

Binds to the DNA with greater affinity than the mutated RARA thus preventing gene silencing

Question 18

What is the point in pharmacogenomics?

Answer 18

Using genetics to determine which patients will respond best to particular treatments