A concurrent canonical and modified miRNAome pan-cancer study on TCGA and TARGET cohorts leads to an enhanced resolution in cancer

Abstract

MiRNA Epitranscriptomics has placed a new layer of complexity in the cancer field. Despite miRNA editing and shifted miRNA isoforms are gaining attention due to recent improvements in next-generation sequencing, a simultaneous study of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modifications, such as A-to-I RNA editing and shifted miRNA isoforms, in >13K adult and pediatric tumor samples across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments datasets. We investigated the differences among canonical miRNAs and a wider comprehensive miRNAome from the expression, clustering, dysregulation, and prognostic perspective. Interestingly, the wider miRNAome boosted clustering results, uniquely outlining cohorts' clinical-pathological features. The abundance of expressed miRNA isoforms directly related to the activation/deactivation of critical carcinogenesis pathways. We found dysregulated modified miRNAs characterized by an opposite expression trend than their canonical counterparts in cancer, potentially impacting their targetome and function. Our study emphasizes the importance of modified miRNAs as potential cancer biomarkers and gene expression regulators, outlining once more the importance of going beyond the well-established paradigm of one-mature-miRNA per miRNA arm.

Transcriptome analysis provides critical answers to the “variants of uncertain significance” conundrum

“…A burgeoning area of transcriptomic research is the detection of noncoding RNAs (ncRNAs), so named because, unlike mRNAs, they are not translated into protein. There is hope that ncRNAs will have diagnostic utility (Ellingford et al, 2021 ; McQuerry et al, 2021 ), particularly for cancer diagnosis (Coley et al, 2021 ; Distefano et al, 2022 ; Lu et al, 2021 ; Osan et al, 2021 ; Ren et al, 2021 ; Sun et al, 2021 ; Tabury et al, 2022 ; Zhu et al, 2021 ). Examples of ncRNAs include miRNAs, small interfering RNA (siRNA), lncRNAs including circular RNAs (circRNAs, which are produced by noncanonical “back‐splicing”), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), and PIWI‐interacting RNA (piRNA) (Hasegawa et al, 2021 ; Junqueira‐Neto et al, 2019 ; Mussack et al, 2020 ; Solé et al, 2021 ; Wen et al, 2021 ).…”