1. A practical guide for mutational signature analysis in hematological malignancies
- Author
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Elias Campo, Daniel Leongamornlert, Bachisio Ziccheddu, Peter J. Campbell, Helen Davies, Nikhil C. Munshi, Andrea Degasperi, Serena Nik-Zainal, Hervé Avet-Loiseau, Niccolo Bolli, Francesco Maura, Romina Royo, Ferran Nadeu, Xose S. Puente, Luiza Moore, Degasperi, Andrea [0000-0001-6879-0596], Moore, Luiza [0000-0001-5315-516X], Nik-Zainal, Serena [0000-0001-5054-1727], Apollo - University of Cambridge Repository, Barcelona Supercomputing Center, Universitat de Barcelona, Nadeu, Ferran [0000-0003-2910-9440], and Puente, Xose S. [0000-0001-9525-1483]
- Subjects
0301 basic medicine ,Computer science ,Chronic lymphocytic leukemia ,ADN ,DNA Mutational Analysis ,General Physics and Astronomy ,Datasets as Topic ,Myeloma ,02 engineering and technology ,Cancer--Immunological aspects ,Hematological malignancies ,Cancer genomics ,Leukaemia ,lcsh:Science ,45/70 ,Multidisciplinary ,BRCA1 Protein ,article ,Myeloid leukemia ,High-Throughput Nucleotide Sequencing ,Genomics ,021001 nanoscience & nanotechnology ,Signature (logic) ,3. Good health ,Leukemia ,Leukemia, Myeloid, Acute ,631/208/212 ,Practice Guidelines as Topic ,0210 nano-technology ,Multiple Myeloma ,631/67/1990/804 ,Leucèmia mieloide ,Science ,Mutational signatures ,45/23 ,631/67/69 ,Computational biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,631/67/1990/283 ,631/67/1990 ,medicine ,Humans ,Càncer -- Aspectes immunològics ,BRCA2 Protein ,Haematological cancer ,Whole Genome Sequencing ,Mutació (Biologia) ,Computational Biology ,General Chemistry ,DNA ,Mutation (Biology) ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,030104 developmental biology ,Mutation ,lcsh:Q ,Treatment decision making ,Analysis tools ,Homologous Recombination Deficiency ,Ciències de la salut [Àrees temàtiques de la UPC] - Abstract
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.
- Published
- 2019
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