We describe here the characterization of a mouse model of T-cell lymphoma engineered with telomere and checkpoint defects. In these unstable murine tumours, cytogenetic and copy number analyses reveal a level of genome complexity comparable to that of human solid tumours. The presence of rampant genome instability, and absence of an engineered dominantly acting oncogene, created a model system in which biological selection pressures drive acquired genomic events with potential relevance to human T-cell malignancy and/or cancer in general. In this model, murine cancers acquire widespread recurrent clonal CNAs targeting loci syntenic to alterations present in a human T-ALL as well as a large collection of diverse haematopoietic, mesenchymal and epithelial cancers. The relevance of these non-random syntenic events is supported on several levels, including the presence of syntenic MCRs in more than one human cancer type; the identification of MCRs harbouring known cancer genes; and the identification of somatic mutations in genes within conserved MCRs (FBXW7 and PTEN).
Evolutionarily conserved genomic deletions targeting the FBXW7
loci motivated re-sequencing of them in human and murine T-ALL samples, revealing frequent mutations. FBXW7
mutation has been described in about 5% of colorectal and ovarian cancers42-44
, although its involvement in T-ALL has not been reported previously. As a key component of the E3 ubiquitin ligase that ubiquitinates NOTCH1, loss or mutation of FBXW7
is expected to be functionally equivalent to PEST domain mutation of NOTCH1
, prolonging NOTCH1 half-life35
. Indeed, a statistically significant anti-correlation is observed between presence of PEST domain mutations in NOTCH1
and presence of FBXW7
mutation in human T-ALL samples. However, the fact that several samples with FBXW7
mutations have wild-type NOTCH1
(5/22) strongly implies that other pathways may be affected by FBXW7
mutations in some cancers. Indeed, FBXW7 is known to promote degradation of other proteins implicated in lymphoma biology such as Aurora A (also known as AURKA), c-Jun (JUN), Cyclin E (CCNE1) and C-myc (MYC)34,35
, the latter of which is also a transcriptional target of NOTCH signalling45
In summary, the compelling synteny between TKO tumours and several human cancers of diverse origins demonstrates that engineered chromosomal instability in the mouse can engender genomic alterations similar to those observed in complex human oncogenomes, providing evidence that murine and human tumours experience common biological processes driven by the orthologous genetic events. These results provide support for the use of such murine models as a guidepost to focus and prioritize re-sequencing efforts in human cancer because cross-species synteny serves as a measure of validation by virtue of the evolutionary conservation and use of different genetic mechanisms (that is, mutation and copy number) involved. Furthermore, the mouse can facilitate the differentiation between somatic CNAs and copy number polymorphisms owing to the fragmentation of syntenic regions in the mouse and human genomes. We conclude that genomically unstable mouse cancer models represent a valuable resource for mining complex human cancer genomes.