Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer

Rosario Distefano, Luisa Tomasello, Gian Luca Rampioni Vinciguerra, Pierluigi Gasparini, Yujia Xiang, Marina Bagnoli, Gioacchino P. Marceca, Paolo Fadda, Alessandro Laganà, Mario Acunzo, Qin Ma, Giovanni Nigita, Carlo M. Croce

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Epitranscriptomic studies of miRNAs have added a new layer of complexity to the cancer field. Although there is fast-growing interest in adenosine-to-inosine (A-to-I) miRNA editing and alternative cleavage that shifts miRNA isoforms, simultaneous evaluation of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modification types, including A-to-I miRNA editing and shifted miRNA isoforms, in >13,000 adult and pediatric tumor samples across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments data sets. The differences between canonical miRNAs and the wider miRNAome in terms of expression, clustering, dysregulation, and prognostic standpoint were investigated. The combination of canonical miRNAs and modified miRNAs boosted the quality of clustering results, outlining unique clinicopathologic features among cohorts. Certain modified miRNAs showed opposite expression from their canonical counterparts in cancer, potentially impacting their targets and function. Finally, a shifted and edited miRNA isoform was experimentally validated to directly bind and suppress a unique target. These findings outline the importance of going beyond the well-established paradigm of one mature miRNA per miRNA arm to elucidate novel mechanisms related to cancer progression.

Original languageEnglish
Pages (from-to)3687-3700
Number of pages14
JournalCancer Research
Issue number20
StatePublished - 15 Oct 2022


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