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Cited by 184Cancer Genomics and DiagnosticsAcute Myeloid Leukemia ResearchChromatin Remodeling and Cancer

A practical guide for mutational signature analysis in hematological malignancies

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Maura, Francesco, Degasperi, Andrea, Nadeu, Ferran, Leongamornlert, Daniel, Davies, Helen, Moore, Luiza, Royo, Romina, Ziccheddu, Bachisio +7 more·2019·Nature Communications
DOI 10.1038/s41467-019-11037-8PMC PMC6611883
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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.

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  • The same indel and structural variant patterns are not observed in multiple myeloma with BRCA inactivation via germline or somatic events.

    “The same patterns are not observed in MM with BRCA inactivation via germline or somatic events, suggesting that the underlying mechanisms might differ from what is seen in solid tumors.49,50”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [49]

    The Results (‘Absence of BRCA-mediated Homologous Recombination Deficiency in MM,’ Fig. 3 caption; page not provided) say that the MM samples differed from BRCA-deficient breast cancers in their indel and structural-variant patterns. The paper does not establish that the MM samples had BRCA inactivation through germline or somatic events, so the claim's restriction to that group is unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The underlying mechanisms in multiple myeloma with BRCA inactivation might differ from those seen in solid tumors.

    “The same patterns are not observed in MM with BRCA inactivation via germline or somatic events, suggesting that the underlying mechanisms might differ from what is seen in solid tumors.49,50”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [49]

    The Results section, “Absence of BRCA-mediated Homologous Recombination Deficiency in MM” (page unavailable), reports that the studied MM samples lacked the BRCA-associated genomic patterns seen in breast cancer. That supports a possible difference from solid tumors, but the paper does not establish that these MM samples had germline or somatic BRCA inactivation. Its conclusion is limited to its cohort and leaves open whether other MM cases show BRCA-like deficiency. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Maura, F., Degasperi, A., Nadeu, F., Leongamornlert, D., Davies, H., Moore, L., Royo, R., Ziccheddu, B., Puente, X. S., Avet-Loiseau, H., Campbell, P. J., Nik-Zainal, S., Campo, E., Munshi, N., & Bolli, N.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • University of Cambridge (GB)
  • Centro de Investigación Biomédica en Red de Cáncer (ES)
  • Wellcome Sanger Institute (GB)
  • Barcelona Supercomputing Center (ES)
  • Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
  • Harvard University (US)
  • University of Milan (IT)
Corresponding author
  • Maura, Francesco
  • Bolli, Niccolò
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-07-05
Volume
10
Issue
1
Pages
2969-2969
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-11037-8
PMC
PMC6611883
OpenAlex
W2954688009
Cited by
184
References
7
Citations by year
2026: 6 · 2025: 13 · 2024: 23 · 2023: 30 · 2022: 35 · 2021: 41 · 2020: 31 · 2019: 5
FWCI
8.86
Type
journal article
Language
en
Update notices
correction (2019-07-25)
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  • PubMed Central (publishedVersion, cc-by)
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  • Consultation of the Doctoral Thesis Database (TESEO) (Ministerio de Educación, Cultura y Deporte) (submittedVersion, cc-by-nc-nd)
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  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • U.S. Department of Veterans Affairs (I01 BX001584, I01BX001584-01)
  • Memorial Sloan-Kettering Cancer Center (P30 CA008748)
  • Università degli Studi di Milano (Horizon 2020)
  • Cancer Research UK (C60100/A23916, 22597, A23433, 25274, A25274, C60100/A25274, 23916, S_3369, 22932, C60100/A23433, 23433, A23916, 27815, C60100/A27815)
  • European Commission (PMP15/00007, HORIZON2020)
  • Generalitat de Catalunya (2017-SGR, 2017-SGR-1142)
  • Ministerio de Economía y Competitividad (PMP15/00007, BES-2016-076372, SAF2017-87811-R)
  • Institució Catalana de Recerca i Estudis Avançats
  • Associazione Italiana Contro le Leucemie-Linfomi e Mieloma
  • Società Italiana di Ematologia Sperimentale
  • Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona
  • National Institutes of Health (P01-155258, I01BX001584-01, I01-BX001584, CA008748)
  • Agència de Gestió d'Ajuts Universitaris i de Recerca (2017-SGR-1142)
  • Instituto de Salud Carlos III (AGAUR 2017, PMP15/00007)
  • European Regional Development Fund (SAF2017)
  • National Cancer Institute (P30CA, 008748, CA008748, P50CA100707, P01155258, P30CA008748)
  • H2020 European Research Council (817997)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
mutational signatures, hematologic malignancies, multiple myeloma, chronic lymphocytic leukemia, acute myeloid leukemia, hypermutation, BRCA1/BRCA2, homologous recombination deficiency, whole genome sequencing, reproducibility
MeSH terms
Whole Genome Sequencing, DNA Mutational Analysis, Humans, Multiple Myeloma, Mutation, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Myeloid, Acute, Practice Guidelines as Topic, Computational Biology, BRCA1 Protein, BRCA2 Protein, High-Throughput Nucleotide Sequencing, Datasets as Topic

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