Integrative genomics reveals molecular and clinical heterogeneity in central nervous system primitive neuroectodermal tumors in children.

Through advances in genome science, we are becoming increasingly aware that tumors that appear identical under the pathologist's microscope can be very different in their genetic composition and clinical behavior. Pediatric embryonal brain tumors share a characteristic histological feature—densely packed sheets of cells with hyperchromatic nuclei and scant cytoplasm. Despite their common appearance, however, embryonic brain tumors are a diverse set of tumors, including medulloblastomas and atypical teratoid rhabdoid tumors, which arise in the hindbrain structures in the posterior cranial fossa, and central nervous system primitive neuroectodermal tumors (CNS PNETs), which arise in the cerebral hemispheres. Picard and colleagues recently published results of an international study of 142 CNS PNETs collected from 20 hospitals in nine countries (1). The global scope of the collaboration made it possible to accrue a large number of these uncommon tumors, which account for only 3-5% of pediatric brain tumors. The investigators made the striking discovery that CNS PNETs do not make up a single disease, but rather distinct tumor subgroups. The heterogeneity of CNS PNETs became apparent when the research team examined the gene expression profiles of these tumors and observed three distinct groups. Group 1 tumors showed increased expression of genes associated with self-renewal of embryonal and neural stem cells, like LIN28 and CRABP1. In group 2 tumors, by contrast, genes involved in the differentiation of neural stem cells into oligodendrocytes, like OLIG2, were expressed at high levels. Group 3 tumors showed decreased expression of neural differentiation genes and increased expression of epithelial and mesenchymal differentiation genes, like COLA2 and COL5A, which encode collagen subunits. Of great practical significance was the discovery that antibody markers could detect expression of LIN28 and OLIG2 reliably in tissue sections, making it possible to classify tumors by conventional immunostaining using these two markers alone. When the tumors were divided into these three groups based on gene expression profiling or immunostaining for LIN28 and OLIG2, the patients showed significantly different ages and treatment responses. Group 1 tumors (LIN28 + /OLIG2-, primitive neural type) occurred in infants and responded poorly to treatment. Group 2 tumors (LIN28-/OLIG2 + , oligoneural type) and group 3 tumors (LIN28-/OLIG2-, mesenchymal type) occurred in older children and took a less aggressive clinical course. It is tempting to attribute the short survival times in young children to the widely accepted practice of sparing infants from the neurotoxic effects of therapeutic radiation. Nevertheless, the fact that …