Hospital for Sick Kids in Toronto researchers are reporting that focused RNA sequencing can detect clinically actionable alterations in 87% of tumors and supply decisive findings the place DNA-seq both fails, returns no variant, or just isn’t informative.
Most cancers remedies have seen super enhancements lately, partially on account of extremely particular concentrating on and diagnostic methods.
DNA-based strategies dominate molecular most cancers diagnostics however battle to detect gene fusions and assess splice web site penalties. RNA sequencing permits delicate fusion detection and direct evaluation of transcript-level disruption attributable to splicing mutations.
Within the examine, “Medical utility of focused RNA sequencing in most cancers molecular diagnostics,” printed in Nature Drugs, researchers applied a focused RNA-seq assay to judge 2,310 tumors throughout central nervous system, stable, and hematopoietic cancers.
Of the two,310 tumors submitted for evaluation, 110 (4.8%) failed high quality management, primarily on account of inadequate RNA. Amongst samples assembly high quality thresholds, sequencing was profitable in 99.6%.
Oncogenic variants have been recognized in 74% of tumors, with a further 13% categorised as pertinent negatives—bringing complete scientific utility to 87%.
Amongst constructive instances, 40% carried single nucleotide variants (SNVs) or indels, 32% fusions, 2.5% different structural variants, and 5% confirmed a number of lessons. Fusions have been 1.8 instances extra frequent in youngsters, whereas SNVs have been 1.6 instances extra frequent in adults.
Amongst 103 samples with matched DNA sequencing, RNA-seq detected 93.3% of oncogenic variants. Variant allele frequencies between RNA-seq and DNA-seq confirmed sturdy correlations.
Amongst tumors sequenced with diagnostic intent, 37 obtained new diagnoses, representing 1.9% of evaluable instances. A further 11 tumors have been reclassified based mostly on the presence or absence of diagnostic alterations, bringing the entire to 48 revised diagnoses.
Central nervous system tumors accounted for 30 of the 48 revised diagnoses. In 13 instances, RNA-seq reclassified ependymoma as glioma, astroblastoma, or paraganglioma. Seven low-grade gliomas have been re-diagnosed as diffuse midline glioma, H3 K27-altered, based mostly on identification of H3K27M mutations.
5 stable tumors have been reclassified, together with one initially recognized as metastatic Wilms tumor, re-identified as clear cell sarcoma of the kidney following detection of a BCOR inside tandem duplication. One other case, beforehand examined with destructive fusion outcomes, was revised to dermatofibrosarcoma protuberans after RNA-seq recognized a canonical COL1A1::PDGFB fusion.
Eight tumors have been reclassified not by detection of a brand new alteration however by ruling out anticipated diagnostic options. In every case, RNA-seq excluded defining molecular markers of the histologic prognosis, resulting in re-evaluation of tumor classification.
In complete, 94 of 104 sufferers thought of for focused remedy obtained remedy based mostly on RNA-seq findings. MAPK pathway inhibitors, tyrosine kinase inhibitors, and immune checkpoint therapies have been mostly used.
Fusions alone defined oncogenesis in 86% of fusion-driven tumors, lots of which lacked extra alterations. RNA-seq succeeded throughout all tumor sorts and tissue codecs, together with degraded FFPE samples.
Researchers conclude that focused RNA-seq can function a stand-alone molecular diagnostic with excessive yield, minimized price, and broad scientific applicability.
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Extra info: Robert Siddaway et al, Medical utility of focused RNA sequencing in most cancers molecular diagnostics, Nature Drugs (2025). DOI: 10.1038/s41591-025-03848-8
