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.

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

“…Second, there are intrinsic differences in the stability of human and mouse cancer genomes. 71 Human cancer genomes are typically structurally complex, with numerous regions of focal chromosomal gain and loss; however, only a small subset of these copy number changes affect driver genes ( Figure 2). In contrast, mouse cancer genomes tend to have whole chromosome gains or losses, with few focal copy number variations.…”

Aberrant signaling in T-cell acute lymphoblastic leukemia: biological and therapeutic implications

“…However, results from our lab show that non-deletional inactivation of PTEN is a major contributor to hyperactivation of PI3K/Akt in primary T-ALL samples (Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M, Nowill AE, Leslie NR, Cardoso AA, Barata JT, unpublished data). PTEN mutations resulting in protein truncation have been identified more frequently in T-ALL cell lines established from relapsed patients (30.4%) than in diagnostic clinical specimens (5.2%), which suggests that PTEN deletion is a late event in human T-ALL (25). In contrast, recent studies using mouse models have shown that PTEN deregulation is important at early stages of leukemogenesis.…”

“…Nevertheless, no activating mutations of PI3K and/or Akt have been described in T-ALL. It has been suggested that PI3K/Akt pathway over-activation results from PTEN protein downregulation and/or SHIP mutations (25,26). However, results from our lab show that non-deletional inactivation of PTEN is a major contributor to hyperactivation of PI3K/Akt in primary T-ALL samples (Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M, Nowill AE, Leslie NR, Cardoso AA, Barata JT, unpublished data).…”

High-content analysis of cancer genome DNA alterations

“…Nedd9 encodes a signaling protein that enhances invasion and metastasis when overexpressed in melanocytes [26]. In the future, introduction of genomic instability into mouse models will enable increased utility of this crossspecies approach [27].…”