RNA Sequencing Improves Gene Fusion Detection for Childhood Cancer Diagnostics

Analysis of whole tumor RNA in children with cancer significantly increases the detection of gene fusions, which can provide information concerning the exact cancer type, the aggressiveness of the tumor, and the possible benefit of targeted drugs.

Chromosomal rearrangements in the genomes of tumor cells can lead to the formation of chimeric transcripts or gene fusions. It is estimated that gene fusions play a key role in the tumorigenesis and metastasis in 20% of all human cancers. Within pediatric oncology, hematologic cancers and sarcomas are characterized by numerous potential fusions. Thus, detecting gene fusions is crucial for accurate diagnosis, prognosis, and determining therapeutic targets.

Toward this end, investigators at the Princess Máxima Center for Pediatric Oncology (Utrecht, the Netherlands) first performed RNA sequencing on a validation cohort of 24 samples with a known gene fusion event, after which a prospective pan-pediatric cancer cohort of 244 samples was tested by RNA sequencing in parallel to existing diagnostic procedures. This cohort included hematologic malignancies, tumors of the CNS, solid tumors, and suspected neoplastic samples.

This wide-ranging survey was made possible by the opening of the Princess Máxima Center for pediatric oncology in 2018. This research hospital is where all children with cancer in the Netherlands are treated.

The investigators identified a clinically relevant gene fusion in 83 of 244 cases in the prospective cohort. Sixty fusions were detected by both routine diagnostic techniques and RNA sequencing, and one fusion was detected only in routine diagnostics, but an additional 24 fusions were detected solely by RNA sequencing. RNA sequencing, therefore, increased the diagnostic yield by 38%-39%. In addition, RNA sequencing identified both gene partners involved in the gene fusion, in contrast to most routine techniques.

Senior author Dr. Bastiaan Tops, head of the diagnostic laboratory at the Princess Máxima Center for Pediatric Oncology, said, “RNA sequencing was already used before, but only in children who were very ill, and for whom standard treatment had stopped working. In our research hospital setting at the Princess Máxima Center, we have implemented RNA sequencing into standard diagnostics. Our new study shows that this approach is paying off. Because we can look at the full genetic landscape of a child’s tumor at diagnosis, we can discuss possible consequences for treatment with the child’s doctor right away. That means we can offer children with cancer the very best opportunities, based on the latest scientific insights.”

The study was publislhed in the January 27, 2022, online edition of the journal JCO Precision Oncology.

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