Subtypes of rare childhood brain tumor identified

Subtypes of rare childhood brain tumor identified

An international research team has identified four likely new subtypes of a rare brain tumor using molecular techniques that lay the foundation for more accurate diagnosis and tailored therapies for the hard-to-treat cancer. The results are published in the journal Cell.

The research involved the most comprehensive analysis yet of the genetic alterations and other molecular characteristics of primitive neuroectodermal tumors of the central nervous system (CNS-PNET). These rare, aggressive tumors occur in children and adults, but are most often diagnosed in young children and account for about 1 percent of pediatric brain tumors.

CNS-PNET tumors arise from extremely immature and undifferentiated tissue in the central nervous system. The tumors are difficult to diagnose using current microscopic techniques, which has hindered development of precision medicine to improve long-term survival. Currently about 40 percent of young patients with CNS-PNET tumors are alive five years after diagnosis.

Researchers in this study used molecular techniques to compare tissue from 323 tumors classified as CNS-PNET to 211 other well-defined brain tumors.

The investigators found that 61 percent of the CNS-PNET tumors could be reclassified as a different type of brain tumor based on the shared molecular features. In many cases, the reclassification suggested a completely different treatment. The analysis of the remaining CNS-PNET tumors found that a majority fell into one of four distinct subgroups, each with unique recurring genetic alterations, including gene rearrangements, deletions and amplifications.

The findings underscore the importance of incorporating molecular information into the World Health Organization system of classifying brain and spinal tumors.
For this study, researchers analyzed the pattern of chemical tags called methyl groups present on DNA from CNS-PNETs and other well characterized brain tumors.

Such methylation profiles are considered to reflect a tumor's cell of origin and to provide information on how closely tumors with similar microscope appearances are related. Based on the methylome profiles, 61 percent of the CNS-PNET tumors could be reclassified as different tumors of the brain or central nervous system, including high-grade gliomas, ependymomas and atypical teratoid/rhabdoid tumors (AT/RTs). Most of the remaining CNS-PNET tumors could be classified into one of four distinct subgroups based on their methylation profile.

Additional analysis demonstrated that the methylation profiles correlated with other genetic characteristics of the four molecularly distinct CNS-PNET tumor subgroups. In contrast, some tumors from the subgroups were difficult to distinguish using microscopic techniques.

DNA and RNA sequencing of the four likely new CNS-PNET subtypes revealed subgroup-specific signature mutations, including gene deletions, amplifications or rearrangements. Analyses of gene expression data identified other subgroup-specific differences in pathways that are disrupted in tumor cells. The disruptions feature alterations in genes that could be targeted for drug development.

The tumor subgroups also differed in regards to the age and gender of patients as well as the treatment outcome. The findings suggest that the tumors would also respond to different targeted therapies.