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What is 'haploinsufficiency'?

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


Describe, broadly speaking, how translocations can cause cancer.

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


What protein does the fusion gene in Chronic Myelocytic Leukaemia produce?

BCR-ABL1 Tyrosine Kinase


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

Familial Adenomatous Polyposis – nearly 100%
Hereditary Non-Polyposis Colorectal Cancer (Lynch Syndrome) –80%


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

Imatinib – inhibits the BCR-ABL1 tyrosine kinase


What are 'cytogenic changes'?

Visible changes in chromosome structure or number


What is the point in pharmacogenomics?

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


What are the normal functions of tumour suppressor genes?

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


What treatment is available for acute promyelocytic leukemia and how does it work?

All Trans Retinoic Acid (ATRA)
Binds to the DNA with greater affinity than the mutated RARA thus preventing gene silencing


Describe the two hit hypothesis.

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


What is a common manifestation of the second hit?

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 los


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

60% in women
? in men


Explain the cause of Chronic Myeloid Leukaemia.

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


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

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


Describe the patho-genetic mechanism of BRCA genes.

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


Which two genes are involved in the translocation causing acute premyelocytic leukaemia?

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


How does the PML/RARA translocation cause cancer?

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