TY - JOUR
T1 - A practical guide for mutational signature analysis in hematological malignancies
AU - Maura, Francesco
AU - Degasperi, Andrea
AU - Nadeu, Ferran
AU - Leongamornlert, Daniel
AU - Davies, Helen
AU - Moore, Luiza
AU - Royo, Romina
AU - Ziccheddu, Bachisio
AU - Puente, Xose S.
AU - Avet-Loiseau, Herve
AU - Cambell, Peter J.
AU - Nik-Zainal, Serena
AU - Campo, Elias
AU - Munshi, Nikhil
AU - Bolli, Niccolò
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-11037-8
DO - 10.1038/s41467-019-11037-8
M3 - Article
C2 - 31278357
AN - SCOPUS:85068461465
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2969
ER -