Expanding the utility of transcriptome analysis for mutation detection in high-risk childhood precision oncology
Mayoh, C.; Barahona, P.; Lin, A.; Cui, L.; Ajuyah, P.; Altekoester, A.; Lau, L. M.; Khuong-Quang, D.-A.; Sullivan, P.; Senapati, A.; Nagabushan, S.; Sullivan, A.; Omer, N.; Moore, A. S.; Nicholls, W.; Endersby, R.; Gottardo, N. G.; McCowage, G. B.; Dalla Pozza, L.; Hansford, J. R.; Khaw, S.-L.; Wood, P. J.; Trahair, T. N.; Marshall, G. M.; Ziegler, D. S.; Tyrrell, V.; Haber, M.; Wong, M.; Ekert, P. G.; Cowley, M. J.
Show abstract
In precision oncology, whole transcriptome sequencing (RNA-seq) excels at identifying oncogenic fusions. Here, using a cohort of 477 high-risk paediatric tumours, we demonstrate that RNA-seq can identify all mutation classes found previously using whole genome sequencing (WGS) and provides additional functional insights into their pathogenicity. By incorporating reference-guided fusion, and reference-free structural variant (SV) detection algorithms with RNA abundance assessment, RNA-seq identified 96% of SVs and resolved 33 complex SVs that WGS failed to identify. Furthermore, RNA-seq identified 92% of all single nucleotide variants and small insertions and deletions. Importantly RNA-seq informed the pathogenicity assessment in 22% of variants through identification of allele specific expression or the functional consequence of splice-altering variants. The utility of RNA-seq extends beyond fusion identification to the interpretation of mutation pathogenicity and the discovery of important mutations that would otherwise go undetected. We propose that RNA-seq is an indispensable companion to WGS in precision medicine.
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