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

what does inactivation of the TSG result in?

Answer 2

uncontrolled cell division • . Mutation means that the checkpoints that the TSG usually puts in place during the cell cycle are eradicated.

Question 3

what happens when the TRG is mutated?

Answer 3

• the mutation means the protein has a different structure and function - the cells can proliferate in an uncontrolled way

Question 4

what types of genetic changes in cells give rise to cancer?

Answer 4

• point mutations - changes in the chromosome structure

Question 5

what are point mutations?

Answer 5

• silent mutations triplet codes for same protein as before so there is no change in primary structure of protein - mis sense mutations different protein made - non sense mutations becomes a stop codon

Question 6

what is the function of the oncogene?

Answer 6

• the opposite of the tumour suppressor gene - growth and proliferation

Question 7

Describe the two hit hypothesis.

Answer 7

It takes two hits (both TSG alleles 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 (hit one by itself is not enough to give rise to cancer)

Question 8

What is ‘haploinsufficiency’?

Answer 8

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 this is because a single hit causes reduction in the level of transcription

Question 9

what happens in the second hit ?

Answer 9

• the second hit is a large deletion - which removes the TSG in the other chromosome along with a large amount of other genetic material - after the second hit some alleles which used to heterogenous will be removed - this means one allele of the previous gene will stay and appears to be homogenous

Question 10

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

Answer 10

BRCA1 and BRCA2 60% 2-4% of all cancer is caused by BRCA this gives rise to the first hit the second hit is normally caused by somatic delation

Question 11

Describe the patho-genetic mechanism of BRCA genes.

Answer 11

BRCA genes are DNA repair genes (specifically, a process called homologous recombination) 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 12

what are proportions of inherited to sporadic cancer?

Answer 12

• 99% of cancer is sporadic - 1% of cancer is inherited

Question 13

what is the reason for two hit hypothesis’ not being 100% ?

Answer 13

• the patient will inherit the first hit - but because of the second hit they need a mutation in the second allele to cause phenotypic change - people who have inherited one mutated allele have high risk of cancer but its not 100%

Question 14

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

Answer 14

Familial Adenomatous Polyposis – nearly 100% - 1000s of growths of polyps - one or become cancers - mutation of the APC gene Hereditary Non-Polyposis Colorectal Cancer (HNPCC) –80% - 3% - most commonly inherited - 80% of cancer risk in lifetime

Question 15

What are ‘cytogenic changes’?

Answer 15

Visible changes in chromosome structure or number these might be causal or the accumulate during disease progression examples include translocation, deletion, duplication

Question 16

Describe, broadly speaking, how translocations can cause cancer.

Answer 16

The translocation could lead to the formation of two new chromosomes with abnormal morphology a new gene might be made of half of a gene of chromosome 20 and half of chromosome 4 which leads to a new protein which could be ccancerous a new fusion gene that encodes a protein that has oncogenic properties

Question 17

Explain the cause of Chronic Myeloid Leukaemia.

Answer 17

it is a disorder of haemological stem cells and is a result of overproduction of mature form of the blood cells - granulocytes 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 18

What protein does the fusion gene in CML produce?

Answer 18

BCR-ABL1 Tyrosine Kinase

Question 19

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

Answer 19

Imatinib – inhibits the BCR-ABL1 tyrosine kinase - it blocks the ATP binding site of tyrosine kinase which makes it inactive leading to necrosis - it also kills the CML cells - some patients develop resistance to this drug but there is a second (tyrosine kinase inhibitor) so monitoring is important

Question 20

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

Answer 20

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

Question 21

explain cytogenetics :

Answer 21

• looks at chromosomes and counts the number of cells with the chromosomal abnormalities - low resolution

Question 22

explain FISH :

Answer 22

apply fluorescently labelled probes to the genes at the break point -There is a coloured probe for the BCR and a different coloured probe for ABL1. You look for a fusion of the two colours - higher resolution

Question 23

explain RT-qPCR (Reverse Transcriptase Quantitative PCR :

Answer 23

measure of the amount of gene transcript of BCR-ABL1 in peripheral blood.

Question 24

what is the patient management for inherited cancer syndrome?

Answer 24

• check family history - if positive family history then offer genetic screening - if the mutation is positive then offer surveillance

Question 25

Give another example of a translocation causing cancer.

Answer 25

Acute Promyelocytic Leukaemia (APML) Translocation between chromosome 15 and chromosome 17

Question 26

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

Answer 26

Chromosome 15 = PML (Promyelocytic Leukaemia) Chromosome 17 = RARA (Retinoic Acid Receptor Alpha) - it is a balanced chromosome translocation - there is an abnormal accumulation immature granulocytes called promyelocytes.

Question 27

How does this translocation cause cancer?

Answer 27

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

Question 28

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

Answer 28

All Trans Retinoic Acid (ATRA) -(another vitamin A derivative) Binds to the DNA with greater affinity than the mutated RARA thus preventing gene silencing the abnormal protein then dissociates itself from the DNA and hence it is no longer silenced - it is not chemotherapy it does not kill the cells

Question 29

What is the point in pharmacogenomics?

Answer 29

Using genetics to determine which patients will respond best to particular treatments - uses the influence of genetic variation - genetic change on drug response

Question 30

how does pharmacogenetics improve cancer treatment

Answer 30

• pharmacogenetics tests are used to identify which patients are most likely to respond to certain cancer drugs based on the presence or absence of certain somatic mutations.

Question 31

examples of pharmatocogenetics

Answer 31

-o KRAS test with cetuximab for colorectal cancer -EGFR test with gefitinib for non-small cell lung cancer - BCR-ABL1 “T315I” test with dasatinib for chronic myeloid leukaemia