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Genetics (week 9): Special Topics


p117 in notes
genetics of CANCER
cells lose control of cell cycle, 2 families of genes involved-->carcinogenesis
incr risk with age
some ca runs in families
cell changes: high mitotic index (>~15% when N is <5%), cells immortal, telomerase is active, contact inhibition is lost, metastasis, xsomal translocations are common
etio: radiation, chem, viruses
genes are common link

cells lose control of cell cycle, 2 families of genes involved-->carcinogenesis:

ONGOGENES: GAS PEDAL
proto-oncogenes that promote cell division, at least 2 dozen of these normally present
incl GH receptors, transcription promotesrs, G-protein transducers, et al
normal fx if for growth, development, repair
mutations-->oncogenes, gas pedal stays down, uncontrolled mitosis
most mutations are dominant because switching just one copy on produces a cancer
erb codes for epidermal GF
myc involved in xsme translocation in Burkitt's lymphoma, top of p118, rare CA of LNs, 8 and 14 mixup
bringing myc oncogene together with lg gene-->lymphocytes go wild-->lymphoma
also abl, ras
abl in translocation involved in CML, chronic myelogenous leukemia OMIM 608232, 9 and 22 mixup
puts oncogene beside bcr gene, philadelphia chromosome (fused alb-bcr gene) on 22
viruses swipe genes, chicken leukemia virus. est 15% of human ca dt viruses

TUMOR SUPPRESSOR GENES: BRAKE PEDAL
inhibit cell division
usu transcription factors involved in DNA repair
usu considered recessive, damage one you're OK cause you have another
best described: Rb (retinoblastoma), BRCA1, p53
BRCA 1 & 2 getns-->60-80% risk of developing breast cancer

p53
in at least half of all cancers (breast, blad, cx, colon, lung, liver, skin), on xsm 17
indication of aggressive cancer, high fatality rate
tumor suppressor that also can shift cells to more glycolytic based metabolism
"gene of the year" Science mag 1995

Knudson hypothesis: two hit model
carcinogeneis requires multiple mutations: lose brakes and overactive gas
a simple oncogene mutation mb masked by active tumor-suppressor gene
only when enough damage accumulates is there a prob with cell cycle control
mutations accumulate with age
both copies of tumor suppressor must be hit/ mutate for sporadic cancer to occur
but could happen in gamete that one gamete is down by a gene to start with-->familial

requires multiple damages to cell cycle controlling genes incl:
switching on oncogenes via mutation, viral promotion, xsm rearrangement
switching off tumor suppressors via mutation

most ca require release from normal constraints of number of mitotic cycles
extending the "Hayflick limit" of ~50
requires activation of telomerase, adds telomeres back on
babies have long telomeres
injx telomerase: fountain of youth or cancer genesis??

most ca sporadic, not usu inherited
some ca do appear to be familial

BURKITTS LYMPHOMA
OMIM 113970
rare CA of lymph seen in Africa usudt transloc btw xsms 8 & 14
30-50% of childhood lymphomas, 1-2% of adult cases
brings myc oncogene under promoter of an lg gene

CHRONIC MYELOGENOUS LEUKEMIA
OMIM 608232
rare, approx 1/500 cancers, more in elders
usudt transloc btw xsm 9 & 22
activates abl oncogene

NUTRITIONAL GENETICS
new field, rapidly developing, not well understood
4-6 ways that genes enter the picture (beyond basic anabolism)

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