Cancer Genetics

Somatic mutationTransformation to malignant cell needs 5-6 mutationsThese could cause  abnormal proliferation avoidance of apoptosis reduce stability of the genome Clonal EvolutionMutation 1Occurs in stem cell/progenitor (slightly more differentiated stem cell)/differentiated cellGrowth of genetically homogenous benign lesion Mutation 2Targets one of the cells of the benign lesionGrowth of a more malignant and invasive cloneMutation 3Targets cells within the malignant subcloneThese cells are further transformed so that genetically independent subclones can coexist within the tumourMutation 4Tumour entirely taken over by cells that behave as cancer stem cells

Proto-Oncogene = normal gene that performs regulatory functions within a cell (potential to become oncogene)Oncogene = cell whose action promotes cell proliferation - cancer5 classes: Secreted Growth Factors Cell Surface Receptors Components of intracellular signal transduction systems  DNA-binding nuclear proteins Components of cell cycle machinery Activation of Oncogenes Normally somatic (rather than germline, as this would likely be lethal) May get amplification of an oncogene - this could be duplications on the chromosome or small extra chromosomes Can be activated by point mutation - could be in the gene causing gain of function, or in a regulatory element causing overexpression Chromosomal rearrangements - can cause chimeric oncogenes by bringing together two distant exons (e.g. Philadelphia chromosome - translocation > chimeric oncogene > chronic myeloid leukaemia), OR upregulation of an oncogene can occur by bringing it close to an active promoter  

RETRET is a proto-oncogeneA gain of function mutation in this gene can lead to cancerMutations can be somatic or germline - high chance of medullary thyroid carcinoma

Clonal Evolution

Oncogenes