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Path - Application of Molecular Pathology (i) (Uses of molecular pathology…
Path - Application of Molecular Pathology (i)
cancer usually develops from a no. of genetic switches
e.g. Colonic carcinoma multistep pathway of neoplasia (Vogelstein's theory)
multiple mutations correlating with the stages of evolution from an adenomatous polyp -> carcinoma
different pathways activated
Uses of molecular pathology
Dx
breast cancer oncotype Dx
ER
if +ve with respond to tamoxifen
HER2
gene on chromo 17
part of EGFR (Her1) family
activates Ras
also over expressed in gastric cancer
IHC tests for it
v accurate
4 scores
0-1: -ve for Tx
2: uncertain, use FISH to confirm
3-4: +ve for Tx (trastuzumab/herceptin)
CR cancer: Kras
BRAF
melanoma
paed CNS tumours
oncogene
codes for mutated RAF
serine/threonine protein kinase
normally activated by Ras
will respond to vemurafenib + dabrafenib
non-small cell lung cancer
Anaplastic Lymphoma Kinase (ALK)
ROS1 (oncogene, tyrosine kinase R)
EGF R rarely
crizotinib = ALK + ROS1 inhibitor
follicular lymphoma
t(14;18)
BCL2 over activation
CML
t(19;22)
BCR-Abl
Philadelphia chromo
GIST: c-kit
Burkitt's lymphoma: t(8;14)
translocations in certain sarcomas
e.g. Ewing's sarcoma
bones / cart / Ns
difficult to Dx (could also be synovial sarcoma) so await molecular analysis
Prognosis
translocation in small cell lymphocytic lymphoma: poor
mutant P53: worse
17p13 deletion in MM: worse
Prediction
by understanding carcinogenesis targeted/personalised Tx can be devised
right drug for right patient
specific pathways of cell division
allow comparison between molecular profile of cancer cells + normal cells
helps us understand how neoplasms grow + develop
Targeted tx
less SEs
some block membrane Rs
monoclonal Igs
"ab"
some block signalling pathways
small molecule inhibitors
"ib"
relies on different molecular behaviour of tumour cells vs normal cells
associated with a companion/complimentary diagnostic
Chemo tx
acts by preventing division
tumours that rapidly divide respond well (e.g. leukaemia, germ cell tumours)
toxic to dividing cells (causes apoptosis)
non-targeted
non-tumour rapidly dividing cells also killed, leading to SEs
BM suppression
GIT upset
alopecia