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Molecular pathology of endometrial carcinomaDr James Duhig
Can form ever fully inform us of function?
Molecular pathology
Tumours defined by their molecular abnormality
CML
GIST
Ewing’s sarcoma
Synovial sarcoma
Epithelial cancers typically have multiple genetic abnormalities
Molecular pathology
EGFR mutation - NSCLC
BRAF V600E mutation - melanoma
KRAS – colorectal carcinoma
Molecular pathologyEndometrial carcinoma
Molecular alterationsMSI
PTEN
KRAS
PIK3CA
Beta-catenin
P53
LOH in several chromosomes/aneuploidy
STK15, P16, E-Cadherin, HER2
Molecular pathologyEndometrial carcinoma
Type 1 tumours (low-grade estrogen dependent endometrioid carcinomas)
MSI, PTEN, KRAS, PIK3CA, Beta-catenin
Type 2 tumours (Mainly serous and clear cell)
P53, LOH, STK15, P16, E-Cadherin, HER2
Microsatellite instability
Occurs in 75% of EC associated with HNPCC
25-30% of sporadic EC (secondary to MLH-1 promotor hypermethylation)
MSI associated mismatch repair deficiency leads to accumulation of many mutations including in STR’S (microsatellites) located within coding sequences of genes
Associated with high histologic grade and earlier presentation in inherited form
PTEN
Phosphatase and tensin homolog – tumour suppressor gene preventing cells from growing and dividing too rapidly
40% of EC show LOH of PTEN
37-61% of endometrioid carcinomas show PTEN mutations.
60-80% of MSI positive tumours have PTEN mutations
PTEN
Identical PTEN mutations occur in coexisting hyperplasia's suggesting an early event in tumour progression
Some data suggests an association with favorable prognostic factors
PIK3CA
Mutations contribute to alterations in PI3K-AKT pathway
Mutations in exon 9 – mostly low grade endometrioid tumours
Mutations in exon 20 – high grade tumours – worse prognosis
Beta-catenin
Component of the E-cadherin-catenin unit
Plays a role in cell differentiation and maintenance of normal tissue architecture
Mutations occur in 14-44% of EC
Alterations described in endometrial hyperplasia with squamous morules
Probably associated with a good prognosis
Non-endometrioid carcinomas
P53 -90%
Loss/reduced expression of E-cadherin – 80-90%
HER2 amplification 30%
Widespread chromosomal gains and losses - aneuploidy
High grade endometrioid carcinoma and mixed tumours
Confound the dualistic model
Appear to originate from endometrioid carcinomas at a molecular level
Some pure non-endometrioid tumours show MSI, along with alterations in PTEN, K-RAS and beta-catenin suggesting an endometrioid origin
Gene expression profiles
Can look at the expression patterns of thousands of genes at a time.
Revolutionized breast cancer classificationLuminal A
Luminal B
HER2 positive
Basal like
Gene expression Endometrial carcinoma
Confirms a dualistic model
Endometrioid tumoursOverexpression of genes under cyclic hormonal regulation and endometrial homeostasis
Type 2 tumoursOverexpression of genes involved in mitotic spindle regulation and genes associated with aneuploidy and aggressive behavior
Gene expression Endometrial carcinoma
High grade endometrioid tumours and mixed tumours cluster with the type 2 tumours
Gene profilesMSI
MSI and MSS tumours appear to have distinct gene expression profiles
392 genes showed different expression at a high statistical value
In MSI tumours down regulation of SFRP1 and SFRP4
SFRP1 shows tumour suppressor activity
Down regulated in several malignancies
Gene profilesEndometrium v OvaryClear cell carcinoma
Similar profiles regardless of site of origin
Endometrioid and Serous carcinomaStriking differences between the 2 sites
Carcinosarcoma
Probably evolve from endometrial carcinomas through epithelial-to-mesenchymal transformation (EMT)
Epithelial cells lose polarity and cell-cell contacts
Reorganise cytoskeleton
Express mesenchymal markers
EMT can be induced by various signals and pathways leading to repression of E-cadherin
Transiently seen in myometrial invasion in conventional EC, permanent in MMMT
MicroRNA
Small non-coding single-stranded RNA molecules regulating expression of target genes
Repress translation or lead to degradation of mRNA of target gene
2000 thousand identified
Each miRNA targets several hundred genes and a single gene can bind multiple miRNAs
MicroRNA
Dysfunctional expression of miRNA a frequent attribute of malignant behavior
May act as – Oncogenes – miR-155
Tumour suppressor genes – miR-15a and miR-16
Targeted therapies
Targeted therapies - UPSC
Her2(C-erb-B2)Transmembrane protein
Overexpression associated with cancer cell proliferation, poor survival and resistance to therapy in multiple human tumours
Overexpression in 20-50% of UPSC and correlates with gene amplification by FISH
Her2(C-erb-B2)
Herceptin (Trastuzamab)GOG 181b
Advanced/recurrent EC of any histology
HER2 2+,3+ immunoperoxidase or FISH positive
No demonstrable single agent activity
Some case reports of significant partial responses
Epithelial cell adhesion molecule - EPCAM
Found in 96% of UPSC
Cell lines highly sensitive to MT201(adectumumab) – mediated antibody dependent cellular cytotoxicity in vitro
Claudin 3&4
Tight junction proteins
Upregulated 8-12 times in UPSC relative to normal endometrium
Epithelial receptors for Clostridium Perfringens enterotoxin(CPE)– a potent cytolytic toxin
Animal models have shown some response to CPE
Kallikrein 6 & 10
Serine proteases
PSA and kallikrein 2 are prostate cancer biomarkers
Kallikrein 6 &10 are present in high levels in the circulation of some ovarian cancer patients and correlate with chemoresistance and poor prognosis.
Highly expressed in UPSC – May serve as biomarkers or potential therapeutic targets
Targeted therapies - UPSC
Human immunoconjugate molecule
IL-6
av-integrins
Trophoblast cell-surface marker
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