Cancer Genetics and Genomics Flashcards
Clonal disorder
All cells in a tumor arise from a single cell whose growth control has gone wrong
Properties of Malignant Cells
Immortal
Grow more rapidly than normal cells of the same origin
Fail to exhibit normal cell-cell interactions
Multi-hit hypothesis
Numerous genetic abnormalities must accumulate to promote the evolution of a tumor
Proto-oncogenes
Genes that encode proteins that are integral for the normal growth of the cell, particularly those involved in cell-cell interactions, cell cycle, and signal transduction
Oncogenes
Genes that have undergone mutations such that the proteins they encode no longer function appropriately in the cell –> unregulated cell growth and proliferation
Gleevec
Used for treatment of chronic myelogenous leukemia b/c of its ability to selectively inactivate the ber-abl fusion kinase but not the normal abl kinase
Result of a gain-in-function mutation?
B/c gain-of-function mutations that interfere with proper regulation of proto-oncogenic activities or that amplify the # of copies of proto oncogenes can lead to disregulation of the oncogenic activity
Why do oncogenes act in a dominant fashion at the cellular level?
Only one of the 2 genes homologs needs to be defective in order for the protein to cause problems in the physiology of the cell
Proteins encoded by oncogenes?
growth factors, growth factor receptors, signal transduction molecules, nuclear transcription (same as proto-oncogenes)
Onco-miRs
miRNA molecules that are responsible for the post-transcriptional regulation of upwards of 200 unique genetic targets per miRNA gene
Some the miRNAs act as oncogenes and inhibit large numbers of tumor suppressor genes
Tumor suppressor genes
Genes that encode proteins whose normal physiological role is largely to prevent the rampant proliferation of cells
are loss-of-function mutations that act in a recessive fashion at the cellular level
*both copies of the tumor suppressor gene must be inactivated in order for tumorigenesis to occur
Caretaker genes
Tumor suppressors
DNA repair genes
Gatekeeper genes
Tumor suppressors
Cell cycle checkpoint genes
Xeroderma Pigmentosum
Mutation in genes required for nucleotide excision repair
Sensitive to UV radiation
recessive chromosome instability syndrome
Ataxia Telangiectasia
ATM mutation prevents proper DNA damage repair for double stranded breaks
Presence of DNA free ends generates a highly unstable genomic state and these fusogenic ends often associate to create new translocations
Karyotype: long chromosome with many constriction points
recessive chromosome instability syndrome
Fanconi Anemia
Patients harbor genetic lesions in proteins that interact with ATM
Also acutely sensitive to agents that cause double-stranded breaks
Symptoms: bone marrow failure
recessive chromosome instability syndrome
Bloom Syndrome
Mutations in another protein complex that interacts with ATM and Fanconi patients
Symptoms: repeated otitis media and pneumonia, early menopause, a wide variety of cancer susceptibilities
recessive chromosome instability syndrome
RB1- 2 hit hypothesis
Both copies of RB1 must be inactivated to promote tumor development
*incomplete penetrance b/c some people with the predisposition of rb do not end up getting the tumor even though high chance that it you have 1 mutated copy, the other will also be mutated
Tumor suppressor- familial inheritance
Inherited in apparent dominant fashion
Loss of heterozygosity
Acquiring a hereditary mutation in a tumor suppressor predisposes an individual to these effects
Heterozygous individuals have a higher likelihood of acquiring a mutation (ie: deletion) in the single remaining wild type allele of the gene
ie: p53- Li Fraumeni syndrome
