Identification of full-length circular RNAs linked with therapy resistance of pediatric cancers
Bessiere, C.; Babin, L.; Andraos, E.; Riepl, J. M.; Szymansky, A.; Lodrini, M.; Deubzer, H. E.; Eggert, A.; Quivoron, C.; Rigaud, C.; Verge, V.; Pyronnet, S.; Lamant, L.; Meggetto, F.; Gaspin, C.; Fuchs, S.
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Resistance to cancer treatment remains the leading cause of cancer-related deaths. In tumors with low mutational burden such as pediatric cancers, alternative transcripts, including circular RNAs (circRNAs), have been identified as involved in treatment resistance. However, their isoforms are often missed by commonly used short-read sequencing. Here, we employ long-read sequencing to identify full-length circRNA isoforms associated with resistance in ALK -driven pediatric cancers. Using cell models and a cohort of ALK -translocated anaplastic large-cell lymphoma (ALK+ ALCL) patients, two circRNAs were detected as specifically upregulated in resistant cases and associated with worse disease outcomes. Similar findings were observed in the pediatric cancer neuroblastoma. These circRNAs were also more abundant in liquid biopsies from ALKi-resistant ALK+ ALCL and neuroblastoma patients. This demonstrates that long-read sequencing allows for uncovering disease-relevant circRNA isoforms that could serve as biomarkers for resistance detection in a clinical setting.
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