In this study, 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. We determined that murine and human tumors have common biological processes driven by orthologous genetic events during their malignant evolution. These findings encourage the use of genomically unstable murine cancer models for the discovery of biological driver events in human cancers.