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Mutational Signatures Profiled in Pediatric Cancers

NEW YORK – A team led by researchers in Germany has systematically analyzed mutational signatures across more than two dozen pediatric cancer types or subtypes, providing a look at everything from processes behind the tumors to potential features or vulnerabilities linked to certain tumor subtypes.

Co-senior authors Natalie Jager and Stefan Pfister, researchers affiliated with Hopp Children's Cancer Center Heidelberg, the German Cancer Research Center, and the German Cancer Consortium, and their colleagues suggested that the resulting pediatric cancer mutational signature set "is highly relevant for understanding tumor biology and enabling future research in defining biomarkers of treatment response."

For a paper appearing in Nature Cancer on Thursday, the researchers brought together whole-genome sequence data for 785 matched tumor-normal pairs spanning 27 childhood cancer types or subtypes, which were profiled for the Pediatric Pan Cancer (PedPanCan) effort. From these sequences, they focused in on single-base substitutions (SBS), insertions or deletions (indel), copy number changes, and rearrangements — alterations used to provide a look at mutational signatures present in the pediatric tumors.

"This study establishes the analysis of SBS and [indel] mutational signatures in one of the largest pediatric pan-cancer cohorts based on whole-genome sequencing to date," the authors explained.

In contrast to human cancers considered for prior studies, the team saw a relatively limited repertoire of active mutational signatures in the pediatric tumor set, including nine known indel-based signatures and more than two-dozen SBS-based signatures stemming from everything from APOBEC activity to ultraviolet light exposure.

The analysis also led to a new indel-rich mutational signature dubbed IDN that was marked by an overrepresentation of long insertions in repeat-free parts of the genome. While some of these insertions fell between genes or in intronic sequences, the researchers explained, they tracked other IDN signature insertions to protein-coding portions of genes such as NOTCH1 that have been previously implicated in cancer.

"Since detection of long insertion indels is difficult with standard short-read sequencing data and computational approaches, it is not unlikely that even longer (and potentially even higher numbers of) insertions affect these leukemia genes, but were missed with the current indel calling procedures," the authors speculated.

When it came to known mutational signatures, meanwhile, the team dug into the most closely linked cancer types or subtypes, while exploring the apparent causes for these signatures.

Most neuroblastoma and rhabdomyosarcoma tumors contained reactive oxygen species-related DNA damage signature, for example, which was found at lower proportions across 15 other cancer types and in more than 27 percent of all the cases considered.

More than one-fifth of the tumors were marked by another signature attributed to homologous recombination in the past, though the new data suggested late replication as the mutational signature source, since none of the newly profiled tumors contained clear homologous recombination defects. Yet another signature showed apparent ties to prior treatment, the researchers noted, but did not appear to be pediatric-specific as previously suspected.

Based on these and other results, the authors suggested that "the mutational signature repertoire in 27 childhood cancers provides a valuable resource for further understanding of tumor biology and aids future research in defining biomarkers of treatment response."