Abstract
The implementation of personalised medicine in childhood cancers has been limited by a lack of clinically validated multi-target sequencing approaches specific for paediatric solid tumours. In order to support innovative clinical trials in high-risk patients with unmet need, we have developed a clinically relevant targeted sequencing panel spanning 311 kb and comprising 78 genes involved in childhood cancers. A total of 132 samples were used for the validation of the panel, including Horizon Discovery cell blends (n=4), cell lines (n=15), formalin-fixed paraffin embedded (FFPE, n=83) and fresh frozen tissue (FF, n=30) patient samples. Cell blends containing known single nucleotide variants (SNVs, n=528) and small insertion-deletions (indels n=108) were used to define panel sensitivities of ≥98% for SNVs and ≥83% for indels [95% CI] and panel specificity of ≥98% [95% CI] for SNVs. FFPE samples performed comparably to FF samples (n=15 paired). Of 95 well-characterised genetic abnormalities in 33 clinical specimens and 13 cell lines (including SNVs, indels, amplifications, rearrangements and chromosome losses), 94 (98.9%) were detected by our approach. We have validated a robust and practical methodology to guide clinical management of children with solid tumours based on their molecular profiles. Our work demonstrates the value of targeted gene sequencing in the development of precision medicine strategies in paediatric oncology.
Highlights
Cancer remains the leading cause of death due to disease in children aged >1 year [1]
The genes were selected in widecollaboration with national experts in paediatric oncology patient care covering all areas of paediatric solid tumours
EGFR mutations or ALK rearrangements in lung cancer, BRAF V600E mutations in metastatic melanoma and breast cancer patients harbouring HER2 amplifications are examples of therapeutic biomarkers routinely used in the adult population [36,37,38]
Summary
Cancer remains the leading cause of death due to disease in children aged >1 year [1]. The stratification of patients by genetic profiling using high throughput sequencing has supported adaptive clinical trials [5, 6], and there is an urgent need to translate such opportunities to the treatment of childhood disease. The genomic landscape of paediatric cancer is becoming increasingly well-defined leading to the conclusion that childhood cancers have in general fewer somatic mutations than adults, but that mutations in epigenetic regulators occur at a higher incidence [7,8,9,10,11,12,13,14,15,16,17]. ATRX mutations, TERT rearrangements and MYCN amplification define mutually exclusive molecular subgroups of neuroblastoma, all of which are associated with poor prognosis [21,22,23]. The newly proposed molecular-based medulloblastoma sub-classification defines subgroups, each of which potentially requires a tailored therapeutic strategy [7, 11, 24]
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