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Path - Intro to molecular Pathology (i) (Molecular pathology (in progress,…
Path - Intro to molecular Pathology (i)
intro to surgical/histopathology
1st used for Dx
then prognosis
e.g. staging a malignancy to see how it will behave
determines Tx
now also used for prediction
gene problem = core to every cancer
inherited or not
somatic
germline
BRCA
breast + ovarian carcinoma
APC
FAP - benign polyps progress to CR cancer
Molecular pathology
understanding how DNA, RNA + protein synthesis interact
emerging discipline
examining molecules within tissues/organs/body fluids
better understanding of disease mechanisms (carcinogenesis)
new diagnostic/prognostic methods + markers
in progress
early detection of recurrent/residual disease
screening
gene changes -> protein changes -> pathway signalling changes -> increased propagation -> changes in cell cycle
Tissue-based techniques
IHC
detects altered protein (end product of gene)
sometimes gene normal + protein function abnormal
labelled Ig (brown dye) to target protein
specific binding - won't wash off when tissue is rinsed
e.g. HER2 status in breast carcinoma
predicts patient's response to trastuzumab (herceptin)
nucleic acid probes
detects altered genes
over expressed gene (more than 2 alleles)
more than 2 visible probes per cell
more RNA + hence protein
FISH or C(chromogenic)ISH
examined under fluorescence or bright field microscopy
labelled with fluorophore or chromogen
probe = complimentary to target sequence (will bind when incubated with sequence on a slide)
used when IHC result is equivocal (inconclusive)
detect chromo rearrangements (translocations)
break apart = abnormal
fusion = normal
used to Dx...
lymphoma
e.g. follicular lymphoma
t(14;18)
overactivation of antiapoptotic BCL2
sarcoma
viral infection (probe complimentary to viral nucleic acid)
Carcinogenesis
alterations in 2 broad gene categories
oncogenes
dom, only 1 overactive gene needed
activated by mutation/translocation/amplification
tumour suppressor genes
rec, usually 2 alleles needed to be lost
inactivated via loss of heterozygosity or methylation (epigenetic change, can result in truncated protein)
R tyrosine kinases
high affinity cell surface Rs for many polypeptides GFs, CKs, hormones
kinases transfer phosphate groups from high energy donors (ATP) to substrates (in this case tyrosine) via phosphorylation
leads to cell signalling
phosphatases do the opposite
targeted by tyrosine kinase inhibitors (e.g. imatinib)
Ras
family of proteins expressed in all cells
small GTPases
involved in signal transduction in cell growth, differentiation, replacement + survival pathways
mutation: constitutively active
in 20-25% of tumours (esp CR)
up to 90% in specific types (e.g. pancreatic)
EDGF R ignored
membrane: EDGF R
cytoplasm: Ras -> Raf -> MEK
nucleus: ERK -> cell cycle progression
normally tightly regulated