A practical guide for mutational signature analysis in hematological malignancies

• Published in: Nature communications Vol. 10; no. 1; pp. 2969 - 12
• Main Authors: Maura, Francesco, Degasperi, Andrea, Nadeu, Ferran, Leongamornlert, Daniel, Davies, Helen, Moore, Luiza, Royo, Romina, Ziccheddu, Bachisio, Puente, Xose S., Avet-Loiseau, Herve, Campbell, Peter J., Nik-Zainal, Serena, Campo, Elias, Munshi, Nikhil, Bolli, Niccolò
• Format: Journal Article Publication
• Language: English
• Published: London Nature Publishing Group UK 05.07.2019; Nature Publishing Group; Nature Research; Nature Portfolio
• Subjects: 45/23; 45/70; 631/208/212; 631/67/1990; 631/67/1990/283; 631/67/1990/804; 631/67/69; Acute myeloid leukemia; Aspectes immunològics; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Cancer; Chronic lymphocytic leukemia; Ciències de la salut; Computational Biology - methods; Computational Biology - standards; Càncer; Datasets as Topic; Decision analysis; DNA Mutational Analysis - methods; DNA Mutational Analysis - standards; Gene sequencing; Genomics; Hematological malignancies; Hematology; High-Throughput Nucleotide Sequencing - methods; High-Throughput Nucleotide Sequencing - standards; Homologous recombination; Homology; Humanities and Social Sciences; Humans; Immunological aspects; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Myeloid, Acute - genetics; Lymphatic leukemia; multidisciplinary; Multiple myeloma; Multiple Myeloma - genetics; Mutation; Mutational signatures; Myeloid leukemia; Pathogenesis; Practice Guidelines as Topic; Science; Science (multidisciplinary); Signature analysis; Signatures; Whole Genome Sequencing - methods; Whole Genome Sequencing - standards; Àrees temàtiques de la UPC
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11037-8

Analysis 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. Mutational signature analysis provides important information about the mutational processes underpinning different stages of tumorigenesis. Here, the authors compare publicly available signature extraction tools and suggest a framework for the generation of accurate and reproducible signature data.