Chromosomally unstable mouse tumors have genomic alterations similar to diverse human cancers
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Transcript of Chromosomally unstable mouse tumors have genomic alterations similar to diverse human cancers
Chromosomally unstable mouse tumors have genomic alterations similar to diverse human cancers
Journal Club14.09.2007
Introduction
• A hallmark of human cancer is highly disorganised, unstable genomes driven by alterations in multiple pathways. Single gene mouse models of cancer development have, in general, not faithfully recapitulated this facet of human disease leading to restrictions on their utility in comparative cancer genomics.
Generation of murine lymphoma model
• Terc, Atm and Trp53 mutant mice were cross-bread. Designated TKO– Terc: stabilize chromosome– Atm: maintain DNA integrity – Trp53: tumor suppressor gene
• Trp53+/- and Trp53-/- mice were more susceptible to develop lymphomas and at a faster rate than Trp53+/+
• Trp53+/- derived tumors showed loss of heterozygosis
Spectral karytype analyses• Each chromosome is
visualised with chromosome specific DNA labelled with a fluophore
• Used to identify structural chromosome aberrations
Generation of murine lymphoma model
• Spectral karytype analyses– G0 telomere intact (Terc+/+ and Terc+/-)– G1 – G4 telomere deficient (Terc-/-)
• G1 – G4 are more prone to chromosomal aberration compared to G0
Translocation
• Non-reciprocal– Robertsonian translocation
• acrocentric chromosomes in the human genome: 13, 14, 15, 21 and 22.
• Long arm fusion and loss of short arm
– Dicentric chromosome • Formation of a chromosome with two centromeres
• Reciprocal– Exchange of material between two non-homologous
chromosomes
Comparative Genomic Hybridization (CGH)
Copy Number Alteration
• Copy Number Alteration (CNA) detected by Comparative Genomic Hybridization (CGH) in TKO lymphomas
• Identification of relevant CNA’s. Notch1 and T-Cell receptors (Tcr)
Notch1
Notch1• Re-sequencing of
TKO tumors missing Notch1 genomic rearrangement– Deletion/insertion – Activation of Notch1
and an up regulation of its transcriptional targets
Correlation of TKO lymphoma to human T-Cell acute lymphoblastic leukemia/lymphoma (T-ALL)
• Minimal Common Region (MCR)• Comparison of TKO and T-All MCR by synteny mapping
Synteny
• Preserved order of genes on chromosomes of related species, as a result of descent from a common ancestor.
FBXW7• FBXW7 is deleted in
TKO lymphomas and T-ALL cells
• Fbxw7 is under expressed in TKO lymphomas
• FBXW7 was mutated or deleted in – 48% cell lines – 29% clinical samples
FBXW7• Fbxw7 binds to the PEST
domain in Notch1 and activates degradation of Notch1
• When the PEST domain is mutated there is a less frequent FBXW7 mutation/deletion compared to heterodimerization domains mutation
• Fbxw7 and PEST is part of the same degradation pathway
PTEN• PTEN is deleted in TKO
lymphomas and T-ALL cells
• 30.4% cell lines• 5.2% clinical samples
• Act as a tumor suppressor by inhibiting the phospho-AKT pathway
PTEN
Correlation to other human tumors
• 62% of amplification in 2 or more tumor types
• 53% of deletions in 2 or more tumor types
• 24 genes from the Cancer Gene Consus could be found within the 104 MCR from TKO tumors (17 oncogenes and 7 tumor suppressors)
Conclusion• TKO mouse lymphomas resemble the genomic
alterations observed in human tumors
• Syntenic mapping of TKO lymphomas with human cell lines or patient samples identified known genes relevant in cancer – Fbxw7, Notch1, Tcr and Pten
• TKO mouse can be used as a screening model for identifying genomic alterations relevant in human cancer
Weakest point
• Have they shown that it is the same mechanisms that drive human and murine tumors?
Strongest point
Murine TKO tumor
Identify CNA’s
Compare murine MCRto human MCR in T-ALL
Notch1 and Tcr
Compare murine MCRto human MCR in 6 different tumor types
In 102 syntenic MCR’s 24 known genes involved in
cancer could be found
FBXW7 and PTEN
Breakage Fusion Bridge
• G0 Terc+/- Terc+/+ Atm-/- Atm+/+
• G1 Terc-/- Atm-/- Atm+/+
• G2 Terc-/- Atm-/- Atm+/+
• G3 Terc-/- Atm-/- Atm+/+
• G4 Terc-/- Atm-/- Atm+/+