molecular basis of cancer Flashcards
5 general characterisitcs of cancer
- increased and uncontrolled growth
- immortality
- loss of differentiation
- invasion
- metastasis
what begins cancer
non-lethal genetic damage
- inherited or env.
- single cell and expansion from it
what are genetic requirements for CA
multi-step hits
- change must be permanent and passed on
where does heterogeneity in CA come from
tumor progression and selection for those best able to survive
2 general ways genes are altered in CA
- mutation (inherited or aquired)
2. epigenetics
4 types of mutations
- point
- deletions/insertion
- amplification.copy number alteration
- translocation
- 8 key features of molecular basis of CA
- self-sufficiency of growth signals
- insensitivity to growth-inhibitory signals
- defects in DNA repair
- evasion of apop
- limitless replicative potential
- sustained angiogenesis
- ability to invade and metastasize
- evasion of host immune system
3 types of oncogenes involves in self-sufficiency of growth signals
- oncogenes - promote cell growth in abscence of growth signals
- proto-oncogenes - non-mutated “normal” genes
- oncoprotein - product of oncegenes
what do oncogenes lead to
acceleration of normal growth patterns
5 steps to normal cell prolif that can be hijacked
- binding of GF to receptor
- transient and limited activation of GF receptor
- transmission of transduced signal
- induction and activation of nuclear regulatory factors
- entry and progression through cell cycle
5 types that oncoproteins may be
- growth factors
- GF receptors
- signal transduction molecules
- nuclear regulatory proteins
- cell cycle regulators
what is normal function, mutation, and clinical implication of Her2-neu
normally - growth factor receptor
mutation - many additional copies
clinical - many breast cancers over express and is associated with poor outcome
what is normal function, mutation, and clinical implication of Ret
normally - glial growth factor receptor in neuroendocrine cells - important for tissue migration in fetus
mutation - translocation and fusion product seen in thyroid CA, aquired point mutations
clinical - MEN type 2 and familial thyroid CA
what is normal function, mutation, and clinical implication of Ras
normally - receptor associated signal transduction molecule, normally self-limited by GTPase
mutation - mutated forms in many CA and continued signalling
clinical - testing for Ras in lung CA predicts responses
what is normal function, mutation, and clinical implication of Abl
normally - signal transduction molecule that can be activated without receptor binding
mutation - chromosomal translocation causes Bcr-Abl which is constinutively active (philly)
clinical - chronic myloid leukemia and acute lymphoblastic leukemia, target of imatinib
what is normal function, mutation, and clinical implication of Myc
normally - nuclear regulatory protein, early response gene, increase in activity
mutation - amplification or translocation
clinical - amplification seen in breat, colon and lung, translocation seen in burkitts lymphoma
what is normal function, mutation, and clinical implication of Cyclin-D
ormally - cell cycle regulator - acts with cyclin dependent kinases to move the cell through the cell cycle
mutation - amplification or translocation
clinical - amplification seen in breast, esopha. and liver CA, translocation seen in melanoma and sarcomas
- what is responsible for insensitivity to growth inhibition
tumor supressor genes (brakes) - loss of function in mutations
3 things a tumor supressor gene does
- regulate or halt cell growth
- checkpoints and brakes on cell cycle
- linked to apoptosis pathways
5 things that a tumor supressor may be
- transcription factor
- cell cycle inhibitor
- signal transduction molecule
- cell surface receptor
- regulator of cellular response to DNA damage
4 key tumor supressor genes
- Rb ( cell cycle inhib)
- Cyclin dependent kinase inhibitor (p16)
- APC (inhibitor of cell transduction)
- p53
2 main cell cycle checkpoints for DNA damage
- G1/2 (Rb, p53, ATM, ATR)- assess damage and commit to replication or not
- G2/M (p53) - reassess and repair before mitosis
what is normal function, mutation, and clinical implication of Rb
normally - cell cycle regulator
- blocks entry of cell into S phase
- bind E2F and stops transcription
- if activated then release E2F and transcription occurs
mutation - 2 hits required to mutate Rb - may be inherited or aquired
clinical - retinoblastoma
what is loss of heterozygostiy
heterozygosity does not affect cell behavior, but need both changed to get outcome
