NEW YORK (GenomeWeb) – A team led by researchers at the University of Cologne in Germany has identified telomere maintenance, RAS, and TP53 pathway alterations in neuroblastoma that appear to provide insights into patients' prognoses.
"Our findings may have important implications for the diagnosis and treatment of neuroblastoma patients, which should be validated in future prospective clinical trials," corresponding and co-senior author Matthias Fischer, an experimental pediatric oncology researcher affiliated with the University Children's Hospital of Cologne and the University of Cologne's Center for Molecular Medicine Cologne, and his colleagues wrote in a paper published online today in Science.
Using targeted, exome, or whole-genome sequencing, Fischer's team profiled 416 pre-treatment neuroblastoma cases in an effort to understand the relationship between tumor mutations and clinical phenotypes in these pediatric sympathetic nervous system tumors, which sometimes regress spontaneously but can also progress to become fatal.
From these data — whole-genome or exome sequences on tumor and matched normal samples from 218 pre-treatment cases and targeted sequencing on another 198 pre-treatment tumors — the team focused in on alterations affecting 17 RAS or TP53 pathway genes, including recurrently mutated genes such as ALK that have been described in prior studies.
The researchers saw alterations in one or more of these genes in 74 of the 416 neuroblastomas. Although these alterations spanned tumors classified as high or low risk based on standard criteria such as patient age or MYCN proto-oncogene amplification, they were significantly more common in cases with poor outcomes.
Moreover, they found that neuroblastoma patients with tumors that had alterations linked to enhanced telomere maintenance also tended to have poorer survival patterns, particularly when the telomere maintenance mechanisms were found in combination with mutations affecting the RAS or TP53 pathways.
Telomere maintenance gets a boost from alterations in genes such as MYCN and TERT that influence telomerase enzyme activity, the investigators explained, while an "alternative lengthening of telomeres" (ALT) pathway can be activated by loss-of-function mutations in ATRX.
In their analyses, the researchers identified 52 neuroblastoma cases with MYCN amplifications, 21 cases marked by TERT rearrangements, and 31 cases that involved ALT-associated promyelocytic leukemia nuclear bodies, along with at least eight tumors that contained predicted inactivating ATRX mutations.
On the other hand, patient prognoses were substantially improved when the tumors were telomere maintenance-negative, the team reported. In particular, cases without telomere maintenance-boosting alterations were among those showing spontaneous regression, regardless of whether other risky mutations turned up in the tumors. Event-free survival was also enhanced in individuals who had ALK mutations — rather than other RAS pathway changes — in their tumors.
Based on their findings so far, the authors suggest that it might be possible to get prognostic clues for many neuroblastoma cases with relatively limited tumor genetic testing in the clinic, provided the results from their study stand up to further scrutiny and future clinical trials.
"Assessment of telomere maintenance mechanisms and a limited set of RAS and [TP53] pathway genes may be sufficient to accurately estimate patient risk at diagnosis and to guide treatment stratification," the authors wrote. "In a clinical setting, telomerase activation may be readily determined by examining the genomic status of MYCN and TERT in the majority of cases and supplemented by analysis of TERT expression levels in [MYCN-wild type] and [TERT-wild type] tumors."
Still, the researchers cautioned that tumor classification based on TERT expression alone may be complicated by tumor cell content and other factors, while the presence of ALT-associated promyelocytic leukemia nuclear bodies could provide other prognostic hints.