Next-Generation Sequencing Identifies Potential Actionable Targets in Paediatric Sarcomas

Abstract

Background: Bone and soft-tissue sarcomas represent 13% of all paediatric malignancies. International contributions to introduce next-generation sequencing (NGS) approaches into clinical application are currently developing. We present the results from the Precision Medicine program for children with sarcomas at a reference centre. Results: Samples of 70 paediatric sarcomas were processed for histopathological analysis, reverse transcriptase polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) with a consensus gene panel. Pathogenic alterations were reported and, if existing, targeted recommendations were translated to the clinic. Seventy paediatric patients with sarcomas from 10 centres were studied. Median age was 11.5 years (range 1-18). Twenty-two (31%) had at least one pathogenic alteration by NGS. Thirty pathogenic mutations in 18 different genes were detected amongst the 22 patients. The most frequent alterations were found in TP53, followed by FGFR4 and CTNNB1. Combining all biological studies, 18 actionable variants were detected and six patients received targeted treatment observing a disease control rate of 78%. Extrapolating the results to the whole cohort, 23% of the patients would obtain clinical benefit from this approach. Conclusions: Paediatric sarcomas have a different genomic landscape when compared to adult cohorts. Incorporating NGS targets into paediatric sarcomas' therapy is feasible and allows personalized treatments with clinical benefit in the relapse setting.

Keywords: clinical translation; next-generation sequencing; paediatric sarcomas; precision medicine; targeted drugs.

Figure 1

Distribution of sarcoma type amongst reported cases. DSRCT: desmoplastic small round cell tumour; MPNST: malignant peripheral nerve sheath tumour; MPECN: malignant perivascular epithelioid cell neoplasm; GIST: gastrointestinal stromal tumour; MIT: myo-fibroblastic inflammatory tumour.

Figure 2

Molecular alterations observed in the 27 patients (each column represents one patient). IHC: immunochemistry.

Figure 3

Workflow diagram showing the next-generation sequencing (NGS) process and targeted treatments drawn from the study.