NEW YORK (GenomeWeb) – An international team led by researchers at St. Jude Children's Research Hospital and the German Cancer Research Center has identified four likely new subtypes of primitive neuroectodermal tumors of the central nervous system (CNS-PNET) using molecular diagnostics.
CNS-PNETs arise from extremely immature and undifferentiated tissues in the central nervous system. These tumors are rare and aggressive, and are most often diagnosed in young children. While they account for a small portion of pediatric brain tumors, young patients diagnosed with CNS-PNET tumors have between a 40 to 60 percent chance of survival five years later, according to the National Institutes of Health.
Since CNS-PNETs affect only a very small portion of the global population, the international nature of the new study, published this week in the journal Cell, ensured there was a large enough cohort to study — often a difficulty with studying rare cancers and diseases, Brent Orr, a neuropathologist at St. Jude and co-first author on the study, told GenomeWeb.
Part of the difficulty with diagnosing and treating CNS-PNETs is that it is often difficult to differentiate them from a high-grade glioma tumor, Orr said. This is critical in determining the most effective treatment options for the patient, since CNS-PNETs are treated with full cranial-spinal radiation and high-grade gliomas are typically treated with local radiotherapy, he said.
In their study, the researchers collected tissue from 323 tumors classified as CNS-PNET and tissue from 211 well-defined reference brain tumors not classified as CNS-PNET. They performed DNA methylation profiling on both tissue sample groups present using the Illumina Infinium Human-Methylation 450 BeadChip array.
Based on the methylome profiles, the research team found that 61 percent of the CNS-PNETs could be reclassified as a different type of brain tumor, such as high-grade gliomas, ependymomas, and atypical teratoid/rhabdoid tumor. In many cases, reclassification of the tumors suggested a completely different treatment.
The researchers' analysis of the remaining CNS-PNETs found that a majority fell into one of four distinct subgroups, each with unique recurring genetic alterations, including gene rearrangements, deletions, and amplifications.
The researchers also analyzed and looked for cluster association in the samples to demonstrate that the methylation profiles correlated with other genetic characteristics that made up the four molecularly distinct CNS-PNET subgroups.
They also extracted DNA and RNA from the tissue samples and sequenced them using Illumina platforms to get a fuller genetic understanding of the four CNS-PNET subtypes, revealing subgroup-specific signature mutations. When the researchers also analyzed the gene expression data, they identified other subgroup-specific differences in pathways that are disrupted in tumor cells, which could be targeted for drug development.
The authors did note that tumor subgroups differed in regards to the age and gender of patients as well as the treatment outcome. They believe that this suggests that the tumors would also respond to different targeted therapies.
"The challenge [now] is taking these [molecular diagnostic techniques] and transferring them to the clinical lab," St. Jude's Orr said. "They are not currently clinically validated."
However, Orr and his colleagues indicated that work has begun to develop clinical tests that incorporate molecular markers into classification and diagnosis of CNS-PNETs.