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A practical guide for mutational signature analysis in hematological malignancies

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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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001002274 Cancer Genomics

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00002319622 cram 11.2 GB
EGAF00002319623 cram 11.9 GB
EGAF00002319624 cram 11.8 GB
EGAF00002319625 cram 11.1 GB
EGAF00002319626 cram 11.9 GB
EGAF00002319627 cram 11.7 GB
EGAF00002319628 cram 10.8 GB
EGAF00002319629 cram 11.6 GB
EGAF00002319630 cram 11.4 GB
EGAF00002319631 cram 11.0 GB
EGAF00002319632 cram 11.6 GB
EGAF00002319633 cram 11.7 GB
EGAF00002335820 cram 17.1 GB
EGAF00002335821 cram 17.1 GB
EGAF00002335822 cram 17.1 GB
EGAF00002335823 cram 17.1 GB
16 Files (206.2 GB)