Histologically similar cancers respond differently to treatment. Consequently, significant populations of cancer patients continue to suffer morbidity and mortality while others with apparently similar tumors are cured. Understanding the biology that drives this heterogeneity is crucial if we are to develop effective treatments for all patients. Advanced genomic technologies have enabled us to divide cancer patients into distinct subgroups, often with different prognoses. However unmasking the mechanisms that generate these molecular subgroups has proven difficult, since their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown. This talk will describe a series of recent and ongoing studies in which cross-species genomics approaches have been used to define the cellular and molecular origins of subgroups of brain tumors. By mapping regional and developmental patterns of human brain tumor subgroup gene expression in the developing mouse nervous system, it has been possible to identify variants of normal neural stem cells that share remarkably similar transcriptomes. These similarities in transcriptome reveal candidate cells of origin with a biologic ‘groundstate’ that is highly susceptible to transformation into the corresponding tumor type. Introduction of gene mutations into transcriptome-matched, but not other, normal mouse NSCs generated accurate tumor models of the corresponding human brain tumor subgroup. These models can then be used in high-throughput drug screens to identify subgroup specific treatments.
Citation Format: Richard J. Gilbertson. Mapping cancer origins. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA18.