Cancer in Families and 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

What are the normal functions of proto oncogene

Answer 2

Growth and proliferation: growth factors, transcriptions factors, tyrosine kinases

Question 3

Describe the two hit hypothesis.

Answer 3

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

Question 4

What is ‘haploinsufficiency’?

Give an example.

Answer 4

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.

E.G. some TSGs only require inactivation of just one allele to have a biological effect and give the cell a selective advantage.

Question 5

What is a common manifestation of the second hit?

Answer 5

Loss of heterozygosity – the deletion could remove other genes that are part of a heterozygous pair. This means that that gene then appears homozygous as one of the alleles has been lost

Question 6

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

Answer 6

BRCA1 and BRCA2

60% (breast cancer)

Question 7

Describe the patho-genetic mechanism of BRCA genes.

Answer 7

BRCA genes are DNA repair genes (specifically, a process called homologous recombination).

• the mutation can happen anywhere in the exon and all of it results in producing non-functional proteins.
• the truncated/non-functional protein causes impaired DNA repair and hence mistakes and damage go uncorrected.

Question 8

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

Answer 8

Familial Adenomatous Polyposis – nearly 100%

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

Question 9

What causes FAP and HNPCC

Answer 9

• FAP caused by mutation of APC ( adenomatous polyposis coli) gene which controls cell division- causes growth of 1000s of intestinal polyps- one or more will become cancerous
• HNPCC is caused by mutation of MLH1 or MSH2 (DNA repair genes)

Question 10

What are ‘cytogenic changes’?

Answer 10

Visible changes in chromosome structure or number

Question 11

Describe, broadly speaking, how translocations can cause cancer.

Answer 11

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

Question 12

Explain the cause of Chronic Myeloid Leukaemia.

Answer 12

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 protein tyrosine kinase, which promotes CML.

Question 13

What protein does the fusion gene in CML produce?

Answer 13

BCR-ABL1 Tyrosine Kinase

Question 14

What is chronic myeloid leukaemia

Answer 14

Disorder of haematological stem cells- this is where the genetic change occurs.
-results in the overproduction of mature form of the blood cells- granulocytes

Question 15

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

Answer 15

Imatinib – inhibits the BCR-ABL1 tyrosine kinase by blocking the ATP binding site of tyrosine BCR-ABL1 molecule making it inactive and leading to cell death- killing CML cells.

Question 16

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

Explain the use of this

Answer 16

• Cytogenetic analysis- count the number of cells with the chromosomal abnormality,
• Fluorescence in situ hybridisation - apply fluorescently labelled probes to the genes at the break point. Different colours for BCR and ABL1. You look for a fusion of the 2 colours.
• molecular quantification of the proportion of BCR-ABL1 mRNA transcript in a patient’s blood sample.

Helps guide clinical management.

Question 17

Give another example of a translocation causing cancer.

Answer 17

Acute Promyelocytic Leukaemia (APML) Translocation between chromosome 15 and chromosome 17
Fusion of PML and RARA genes.

Question 18

Which two genes are involved in this translocation?

Answer 18

Chromosome 15 = PML (Promyelocytic Leukaemia) Chromosome 17 = RARA (Retinoic Acid Receptor Alpha)

Question 19

How does this translocation cause cancer?

Answer 19

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
Produces RARA-PML gene product.

Question 20

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

Answer 20

All Trans Retinoic Acid (ATRA) Binds to the DNA with greater affinity than the mutated RARA thus preventing gene silencing.
ATRA does not kill cells- continuous therapy needed as residual stem cells remain.

Question 21

What is the point in pharmacogenomics and give examples?

Answer 21

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

KRAS test with cetuximab for colorectal cancer

EGFR test with gefitinib for nonsmall-cell lung cancer

BCR-ABL1 T315I test with dasatinib for chronic myeloid leukaemia

Question 22

What are DNA repair genes?

Answer 22

Tumour suppressor genes because when they are knocked out DNA fidelity is compromised

Question 23

Explain the difference between somatic and germline mutations.

Answer 23

99% of cancers are sporadic (non-inherited); only 1% have an inherited (“germline”) component.

In sporadic cancers, all genetic aberrations are somatic.