Genetics 4-Cancer in Families and Individuals Flashcards
What are tumour suppressor genes?
Inactivation of the TSG results in uncontrolled cell division. Mutation means that the checkpoints that the TSG usually puts in place during the cell cycle are eradicated.
TSGs are recessive
Abnormality in the oncogene promotes growth.
Normal functions of TSG: Regulating cell division DNA damage checkpoints Apoptosis DNA Repair - if you have an abnormality in a DNA repair gene it won't immediately impact the cell cycle but you acquire some other change which causes changes in the cell cycle.
What are oncogenes
Growth and Proliferation (growth factors, transcriptions factors, Tyrosine Kinases)
What is the two hit hypothesis
You need to have mutated both TSG alleles to give the cells a selective advantage.
Typically caused by a mutation (hit 1) and a more gross change which removes the other allele of the gene (hit 2 is often a larger deletion).
You need at least two genetic changes to give rise to cancer.
Hit 1 reduces the transcript/protein level but is insufficient to cause a phenotypic effect.
Requires inactivation of second allele causing total loss of transcription for the malignant phenotype to be conferred.
What is hapolinsufficency
Some TSGs only require inactivation of just one allele.
Single hit causes reduction in the level of transcript/protein sufficiently to have a biological effect (give the cell a selective advantage).
A 50% reduction in the protein is enough to give the cell a selective advantage. ,
Describe loss of hetrozygosity
one allele deleted the other one has a point mutation so the second one is expressed as if it was homozygous
What is a germline mutation
inheritance of a mutation in germline tissue, usually tumour suppressor.
Only 1% have an inherited (germline) component -
What are BRCA1 and BRCA2 genes role in cancers?
2-4% of all breast cancers caused by germline mutations of BRCA1 and BRCA2 genes.
The normal function of BRCA1/2 is DNA Repair - specifically, a process called homologous recombination.
Also associated with ovarian cancer
Inherited predisposition to colorectal cancer
FAP (Familial Adenomatous Polyposis):
Characterised by growth of 1000s of intestinal polyps - one or more will become cancerous.
Mutation of APC (adenomatous polyposis coli) gene which controls cell division.
Virtually 100% lifetime risk of cancer
HNPCC (Hereditary Non-Polyposis Colorectal Cancer)
3% of all cases
Most common inherited form
Mutation of MLH1 or MSH2 (DNA Repair Genes)
80% lifetime cancer risk
Describe Chronic Myeloid Leukaemia
Characterised by a translocation between Chromosome 9 and Chromosome 22.
Following splicing, the BCR-ABL1 mRNA is formed.
The mRNA is translated to produce BCR-ABL1 protein tyrosine kinase
Imatinib (Glivec) - INHIBITS BCR-ABL1 TYROSINE KINASE
3 different types of quantify different levels of treatment
Cytogenetics - look at the chromosomes themselves and count the number of cells with the chromosomal abnormality which is characteristic of CML. This can only be used in the first 6-12 months because it has a low resolution. It is laborious.
FISH (Fluorescence in situ Hybridisation) - 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. This has higher resolution. When the disease drops to less that 1%, something more sensitive is needed.
RT-qPCR (Reverse Transcriptase Quantitative PCR) - measure of the amount of gene transcript of BCR-ABL1 in peripheral blood. You hope not to detect any transcript whatsoever - many patients achieve this after 18-24 months.
Describe Acute Promyelocytic Leukaemia (APML)
Involves transolcation on chromosome 15 and 17
Simple Treatment - All Trans Retinoic Acid (ATRA) - also a Vitamin A derivative - has a greater affinity for the DNA than the abnormal protein is binding to than the abnormal protein itself.
What is Pharmacogenomics
Emerging branch of pharmacology which deals with the influence of genetic variation and genetic change on drug response.
In cancer treatment, pharmacogenomic 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.
