Session 11: Neoplasia III Flashcards
give examples of inherited susceptibility to tumours
inherited susceptibility: retinitis (xeroderma) pigmentosum - inc. risk of skin cancers during exposure to UV radiation in sunlight
- Ataxia telangiectesia - defective response to radiation damage, profound susceptibility to lymphoid malignancies, people usually die before the age of 20
- Fanconi’s anaemia - dec. marrow function, sensitivity to DNA X-linking agents, multiple congenital abnormalities, predisposition to cancer
give examples of inherited tumours
familial adenomatous polyposis - APC
breast cancer -BRAC1/2
retinoblastoma - RB1
Li-Fraumeni syndrome - p53
retinitis (xeroderma) pigmentosum
inc. risk of skin cancers during exposure to UV radiation in sunlight
Ataxia telangiectesia
defective response to radiation damage, profound susceptibility to lymphoid malignancies, people usually die before the age of 20
Fanconi’s anaemia
dec. marrow function, sensitivity to DNA X-linking agents, multiple congenital abnormalities, predisposition to cancer
functions of proto-oncogenes and the changes that occur in neoplasia
def.: it is a normal gene that can become an oncogene due to mutations/inc. expression
normal function: normal growth and differentiation
the DNA sequence is identical to viral oncogenes
modified by mutation/amplification/translocation to become oncogenes
- these allow the cell to escape normal growth control and become self-sufficient w/o external signals required to grow
- inly one allele of a P-O needs to mutate to cause neoplasia
functions of tumour suppressing genes and the changes that occur in neoplasia
def.: gene that encodes prot.s that suppress growth and cancer
Normally the TSGs encode prot.s that suppress growth -> loss/alterations -> loss of growth suppression
Both alleles need to mutate here to produce neoplasia - Knudson’s 2 hit hypothesis (inheritance of the first hit can inc. susceptibility to cancers
the role of oncogenes: ras, c-myc, c-erbB-2/HER-2 in cancer
Ras: normally transmits growth-promoting signals to the nucleus
-mutant Ras is perm. activated and cont. stim.s cells leading to 15-20% of all cancers, esp. lung and colon cancer
C-myc: Binds to DNA, stim.s synth., amplified (over expressed) leading to neuroblastoma, breast cancer, or translocation between the 8th and 14th chromosome -> Burkitt’s lymphoma
HER-2: encodes for a GF receptor, amplified, leads to ~25% of breast cancers, Herception is comp. antagonist at the HER-2 receptor
the role of TSGs: Rb and p53 in cancer
Rb: passage beyond the R point in the cell cycle is governed by phosphorylation of Rb, defect in both alleles allow the cell to escape the cell cycle control -> retinoblastoma
p53: ‘Guardian of the genome’, approx. 50% of tumours have p53 mutations, encodes a nuclear protein that binds to and modulates the expression of genes important for cell cycle arrest, DNA repair adn apoptosis
stages in carcinogenesis
1 Initiators: carcinogens eg polycyclic hydrocarbons, radiation
- exposure of cell to right amount of carcinogen and the cell has permanently altered DNA damage, capable of making tumour, effect is modified by gen. factors, DNA repair
- initation alone is not sufficient for tumour formation
2 promotors eg hormones, local tiss. responses, immune responses
- can induce tumours in initiated cells, non-tumourigenic on their own, need exposure after initiation, cell changes are reversible if the promotor is removed->cell should return to normal
- enhances prolif.s, esp. in mutated cells, inc. incidence of more mutations -> may lead to cancer
1st stage in carcinogenesis
initiators: exposure of cell to right amount of carcinogen eg radiation, polycyclic hydrocarbon, leads to cell alterations, capable of forming tumours
permanent DNA damage, effect is modified by genetic factors, DNA repair, initiation alone is not sufficient for tumour formation
2nd stage in carcinogenesis
promotors: eg hormones, local tiss. and immune responses
- can induce tumours in initiated cells, non-tumourigenic by themselves, need exposure after initation, cell changes are reversible; if the promotor is removed the cell will repair and return to normal
- enhances proliferation esp. in mutated cells and inc. incidence of more mutations
Radiation link w/ tumour development
wide range of diff. types of damage to DNA eg single/double strand breaks and base damage
- depends on quality and dose of radiation -> if DNA reapir mech.s are overwhelmed and DNA damage is unrepaired -> mutations in TSGs and P-Os can lead to cancer
- Types - Ionising eg Hirohsima - early leukaemia/lymphoid -> late thyroid/breast
- UV - eg squamous and basal cell carcinoma, malignant melanoma
Chemical links w/ tumour development
carcinogens interact w/ DNA in 1 of a no. of ways - some act directly, others need metabolic conversion to an active form
Types: Polycyclic aromatic hydrocarbons: produced by combustion of tobacco, fossil fuels, hydroxylated to active forms, casues lung, bladder and skin cancer (also scrotum in chimney sweeps)
- Aromatic amines: hydroxylated in liver and conjugated w/ glucuronate (P2 drug metab.), deconjugated in urinary tract by urinary glucuronidase -> sits in bladder - bladder cancer, found in rubber and dye workers
- Alkylating agents: eg nitrogen mustards, binds directly to DNA
Viral links w/ tumour development
Hep.B: assoc. w/ hepatocellular carcinoma, viral DNA integrates itself into host cell genome, virus causes liver injury -> regen. hyperplasia, inc. cell divisions gives inc. risk of gen. changes
Epstein-Barr: sometimes a cause of Burkitt’s and some Hodgkin’s lymphoma, nasopharyngeal carcinoma, infects epith. of oropharynx and B cells, viral genes deregulate normal prolif. and survival signals, sets stage for acquisition of mutations
HPV: disrupts normal cell cycle, viral genes incorporated into host cell genome -> drive prolif.
