Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers

Abstract

Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the neoplastic transformation process. Here we engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Along with targeted re-sequencing, our comparative oncogenomic studies identified FBXW7 and PTEN to be commonly deleted both in murine lymphomas and in human T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL). The murine cancers acquire widespread recurrent amplifications and deletions targeting loci syntenic to those not only in human T-ALL but also in diverse human haematopoietic, mesenchymal and epithelial tumours. These results indicate that murine and human tumours experience common biological processes driven by orthologous genetic events in their malignant evolution. The highly concordant nature of genomic events encourages the use of genomically unstable murine cancer models in the discovery of biological driver events in the human oncogenome.

Figure 1. The TKO model

a, Kaplan-Meier curve of thymic lymphoma-free survival for G₃-G₄ TKO mice with varying Trp53 dosage. b, Trp53 loss of heterozygosity assessed by PCR. N, normal; T, tumour. c, Representative FACS profile of a TKO tumour with CD4 and CD8 cell surface marker antibodies. d, Representative SKY images from metaphase spreads from G0 (upper panel) and G1-G4 (lower panel) lymphomas. e, Quantification of cytogenetic aberrations (recurrences) detected by SKY in G0 (blue) and G1-G4 (red) thymic lymphomas. Darker portion of column indicates proportion of non-reciprocal translocations; lighter portion indicates dicentric/robertsonian-like rearrangements. f, Recurrence plot of CNAs defined by array-CGH for 35 TKO lymphomas. The x axis shows the physical location of each chromosome. The percentage of tumours harbouring gains (dark red, log₂ ≥0.3), amplifications (bright red, log₂ ≥0.6), losses (green, log₂ ≤-0.3), and deletions (dark green, log₂ ≤-0.6) for each locus is depicted. Locations of physiologically relevant CNAs at Tcrb, Tcra/Tcrd and Tcrg (arrows), and Notch1 and Pten (asterisks) are indicated.

Figure 2. FBXW7 alterations are common in human T-ALL and conserved in the murine TKO tumours

a, log₂ ratio of array-CGH plots showing conserved deletion of FBXW7 in both mouse TKO and human T-ALL cell lines; FBXW7 is indicated in green. The y axis shows log₂ of copy number ratio (normal, log₂ = 0); amplifications are above and deletions are below this axis; x axis, chromosome position, in Mbp. b, Relative expression level (by real-time quantitative PCR) of mouse Fbxw7 mRNA in murine TKO tumours, with expression in normal thymus (thymus A) set at 1; an independent normal thymus sample (thymus B) was run for comparison. c, Location of FBXW7 mutations in a panel of human T-ALL patients and cell lines. Each marker represents an individual cell line/patient.

Figure 3. Conservation of PTEN genetic alterations in human and mouse T-ALLs

a, Array-CGH plots showing conserved deletion of PTEN in both mouse TKO and human T-ALL cell lines; PTEN indicated in green. The y axis shows, log₂ ratio of copy number (normal, log₂ = 0); amplifications are above and deletions are below the red axis. b, Western blotting for PTEN, phospho-Akt, Akt and tubulin (loading control) in a panel of murine TKO and human T-ALL cell lines. BE13 and PEER are synonymous lines. Samples in red harbour confirmed sequence mutations; samples in blue harbour aCGH-detected deletions. c, CNAs affecting other members of the Pten-Akt axis are shown as log₂ ratio plots for murine TKO tumours. The location of each gene (Akt1/Tsc1) is shown in green.

Figure 4. Substantial overlap between genomic alterations of murine TKO lymphomas and human tumours of diverse origins

a, Characteristics of MCRs from human array-CGH profiles from the indicated tumour types are listed on the left portion of the panel. PDAC, pancreatic adenocarcinoma. The number of TKO MCRs (Amp, amplifications; Del, deletions) with syntenic overlap with the corresponding human CGH data set is indicated on the right side of the panel (P value is based on 10,000 permutations). b, Pie-chart showing numbers of TKO MCRs (indicated within each segment) with syntenic overlap identified in one or multiple human tumour types (indicated by different colours of the segments); left panel, amplifications; right panel, deletions. c,Venn diagram representation of overlap between murine TKO MCRs and MCRs from human cancers of T-ALL, multiple myeloma, or solid tumours (encompassing glioblastoma, melanoma, and pancreatic, lung and colon adenocarcinoma).