1. Chromosomally unstable mouse tumors have genomic alterations similar to diverse human cancers
Journal Club

2. 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.

3. 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

4. Spectral karytype analyses
Each chromosome is visualised with chromosome specific DNA labelled with a fluophore
Used to identify structural chromosome aberrations

5. 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

6. Translocation Non-reciprocal 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

7. Comparative Genomic Hybridization (CGH)

8. 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)

9. Notch1

10. Notch1
Re-sequencing of TKO tumors missing Notch1 genomic rearrangement
Deletion/insertion
Activation of Notch1 and an up regulation of its transcriptional targets

11. 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

12. Synteny
Preserved order of genes on chromosomes of related species, as a result of descent from a common ancestor.

13. 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

14. 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

15. 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

16. PTEN

17. 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)

18. 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

19. Weakest point
Have they shown that it is the same mechanisms that drive human and murine tumors?

20. Strongest point

21. known genes involved in
Murine TKO tumor
Identify CNA’s
Notch1 and Tcr
Compare murine MCR
to human MCR in T-ALL
FBXW7 and PTEN
Compare murine MCR
to human MCR in 6
different tumor types
In 102 syntenic MCR’s 24
known genes involved in
cancer could be found

22. Breakage Fusion Bridge

23. G0 Terc+/- Terc+/+ Atm-/- Atm+/+
G1 Terc-/- Atm-/- Atm+/+
G2 Terc-/- Atm-/- Atm+/+
G3 Terc-/- Atm-/- Atm+/+
G4 Terc-/- Atm-/- Atm+/+