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Neuroblastoma Mutational Processes Uncovered by Whole-Genome Sequencing

NEW YORK – Members of an international research team have identified several mutational processes that appear to reflect the clinical heterogeneity of neuroblastoma, a pediatric solid tumor that affects early nerve cells.

"We hypothesized that co-occurrence analyses of mutational signatures derived from independent variant types may identify new principles of neuroblastoma mutagenesis that explain the differences in variant patterns observed across clinical risk groups," co-senior and corresponding author Anton Henssen, a researcher affiliated with the Max Delbrück Center for Molecular Medicine and Charité Berlin's Experimental and Clinical Research Center (ECRC), and his colleagues reported in Cell Genomics on Thursday.

For their analyses, researchers from the ECRC, the Max Delbrück Center for Molecular Medicine, and other centers in Germany, Spain, and the US started with published whole-genome sequences for 103 neuroblastoma tumor-matched normal sample sets and unpublished tumor-normal genome sequences for another 11 neuroblastoma cases.

By examining a range of alterations — from single nucleotide changes and small insertions or deletions to copy number alterations and complex rearrangements — they began teasing apart the mutational processes at play in high-risk or non-high-risk forms of neuroblastoma with or without MYCN amplifications.

The team noted that the poorest overall survival patterns are found in children with high-risk MYCN-amplified neuroblastoma, while overall survival for high-risk non-MYCN-amplified neuroblastoma falls between these and cases classified as non-high-risk.

"This study analyzed neuroblastoma genomes from clinically heterogeneous patients and classified the mutational processes and genomic rearrangement patterns based on all genomic variant classes," the authors wrote, adding that the study "provides a comprehensive classification of active mutational processes in neuroblastoma, offering new insights into the origin of genomic alterations involved in neuroblastoma genesis and progression."

When the compared mutational profiles in the 21 percent of patients with high-risk, MYCN-amplified neuroblastoma to the 36 percent of patients with high-risk, non-MYCN-amplified neuroblastoma and the 43 percent of non-high-risk cases, the team defined three clinically-relevant clusters. Those results were backed up by ultra-deep genome sequencing on tumor-normal pairs from three dozen more neuroblastoma cases in a validation cohort.

In the subset of high-risk tumors containing MYCN amplifications, for example, the team identified alterations associated with DNA replication stress and slippage. In contrast, high-risk neuroblastomas that did not harbor such MYCN amplifications were more prone to mutational signatures that resulted from homologous recombination deficiency (HRD).

When the investigators focused on neuroblastoma tumors from non-high-risk cases, on the other hand, they unearthed mutational activity involving topoisomerase 1 activity and saw signs of defects linked to chromosomal missegregation.

"Our findings demonstrate that clinical neuroblastoma heterogeneity is associated with differences in mutational footprints across genomic variant classes," the authors wrote, "offering a new perspective on the mutational processes contributing to neuroblastoma genesis and evolution."

Based on these and other results, the researchers suggested that the mutational patterns identified in their current neuroblastoma tumor set could provide clues to understanding and treating diverse forms of the pediatric cancer in the future.

"The three mutational scenarios presented here not only refine our understanding of neuroblastoma's clinical heterogeneity but may also improve our understanding of how mutational processes contribute to the generation of different variant classes in cancer in general," they wrote.