Cancer Genetics Flashcards
What is clinal evolution?
Process by which a cell acquires genetic and Epigenetic changes over time which affect cell proliferation and lead to malignant transformation.
1st mutation - growth of genetically homogenous benign lesion
2nd mutation - growth of more malignant and invasive clone
3rd mutation - genetically independent sub-clones exist within the tumour
4th mutation - tumour taken over by cells that behave as cancer stem cells
What are commonly involved in inherited cancer syndromes?
Germ line alterations that increase chance of developing one or more types of cancer. Usually tumour suppressor genes
What is an oncogene?
Gene whose action promotes cell growth. In normal cell they control cell growth. Mutation cause oncogene conversion from Porto-oncogene to oncogene.
Can be qualitative (affects function) or quantitative (more made) mutations
What are the five broad classes of oncogene?
1) secreted growth factors
2) cell surface receptors
3) components of intracellular signal transduction systems
4) DNA-binding nuclear proteins
5) control of cell cycle machinery
How can an oncogene be activated?
Chromosome rearrangement (quant) Gene amplification (quant) Point mutation (quali)
Give an example chimeric cancer forming chromosome rearrangement
Philadelphia chromosome
Chromosome 9:22 translocation
ABL joined onto the BCR region
Acts via second messengers to stimulate proliferation
What treatments exist for Philadelphia chromosome?
Imatinib
BCR-ABL tyrosine kinase inhibitor
What is RET?
Rearranged during transfection gene
Encodes receptor tyrosine kinase
Expressed highest during embryogenesis, essential for kidney development and maintenance/self renewal of spermatogonial stem cells
Gain of unction mutations associated with 20-40% carcinomas of the thyroid
Germ-line point mutations associated with MEN2 - usually lie at sites that promote dimerisation and favour kinase activity
What therapies exist for RET?
Inhibited by small molecule tyrosine kinase inhibitors
What is a tumour suppressor gene?
Gene that inhibits cell proliferation Both alleles must be inactivated to chance behaviour: - cell cycle deregulation - defective DNA repair - altered cell-to-cell communication
What is Knudsons hypothesis?
Two hit hypothesis
Person who inherits mutant allele must undergo second somatic mutation to initiate tumourogenesis
Persons with inherited may develop cancer in more than one site
Outline retinoblastoma
Rare aggressive childhood tumour 40% inherited RB1 gene If inherit 1 mutant allele then only require one more to be mutated for tumourogenesis Likely in eye due to exposure to UV Develops in both eyes more in inherited
What is loss of heterozygosity?
What are the mechanisms?
Loss of normal function of an allele of a gene in which the other allele was already inactive
Mitotic rearrangement
Deletion of chromosomal region
Gene conversion
Epigenetic gene inactivation
What is Wilms’ tumour?
Undifferentiated mesodermal tumour of intermediate cell mass
Most common Intra-abdominal tumour of childhood (20%)
Sporadic or familial
WT1 gene the tumour suppressor
Chromosome 11
How can miRNA dis-regulation occur in cancer?
Genetic alterations
Epigenetic changes
