Maura, FrancescoDegasperi, AndreaNadeu, FerranLeongamornlert, DanielDavies, HelenMoore, LuizaRoyo, RominaZiccheddu, BachisioPuente, Xosé S.Avet-Loiseau, HerveCampbell, Peter J.Nik Zainal, SerenaCampo, EliasMunshi, NikhilBolli, Niccolò2020-04-012020-04-012019Maura F, Degasperi A, Nadeu F, Leongamornlert D, Davies H, Moore L, Royo R, Ziccheddu B, Puente XS, Avet-Loiseau H, Campbell PJ, Nik-Zainal S, Campo E, Munshi N, Bolli N. A practical guide for mutational signature analysis in hematological malignancies. Nat Commun. 2019; 10(1):2969. DOI: 10.1038/s41467-019-11037-82041-1723http://hdl.handle.net/10230/44132Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data.application/pdfeng© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-019-11037-8Cancer genomicsGenomicsHaematological cancerLeukaemiaMyelomainfo:eu-repo/semantics/openAccess