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A practical guide for mutational signature analysis in hematological malignancies

Author

Listed:
  • Francesco Maura

    (Memorial Sloan Kettering Cancer Center
    University of Milan
    Wellcome Sanger Institute)

  • Andrea Degasperi

    (Wellcome Sanger Institute
    Cambridge University Hospitals NHS Foundation Trust
    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus)

  • Ferran Nadeu

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC))

  • Daniel Leongamornlert

    (Wellcome Sanger Institute)

  • Helen Davies

    (Wellcome Sanger Institute
    Cambridge University Hospitals NHS Foundation Trust
    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus)

  • Luiza Moore

    (Wellcome Sanger Institute)

  • Romina Royo

    (Joint BSC-CRG-IRB Research Program in Computational Biology)

  • Bachisio Ziccheddu

    (Fondazione IRCCS Istituto Nazionale dei Tumori)

  • Xose S. Puente

    (Universitat de Barcelona
    Instituto Universitario de Oncologia (IUOPA), Universidad de Oviedo)

  • Herve Avet-Loiseau

    (IUC-Oncopole, and CRCT INSERM U1037)

  • Peter J. Campbell

    (Wellcome Sanger Institute)

  • Serena Nik-Zainal

    (Wellcome Sanger Institute
    Cambridge University Hospitals NHS Foundation Trust
    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus)

  • Elias Campo

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    Joint BSC-CRG-IRB Research Program in Computational Biology)

  • Nikhil Munshi

    (Harvard Medical School
    Veterans Administration Boston Healthcare System)

  • Niccolò Bolli

    (University of Milan
    Fondazione IRCCS Istituto Nazionale dei Tumori)

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.

Suggested Citation

  • Francesco Maura & Andrea Degasperi & Ferran Nadeu & Daniel Leongamornlert & Helen Davies & Luiza Moore & Romina Royo & Bachisio Ziccheddu & Xose S. Puente & Herve Avet-Loiseau & Peter J. Campbell & Se, 2019. "A practical guide for mutational signature analysis in hematological malignancies," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11037-8
    DOI: 10.1038/s41467-019-11037-8
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    Cited by:

    1. Ryan N. Ptashkin & Mark D. Ewalt & Gowtham Jayakumaran & Iwona Kiecka & Anita S. Bowman & JinJuan Yao & Jacklyn Casanova & Yun-Te David Lin & Kseniya Petrova-Drus & Abhinita S. Mohanty & Ruben Bacares, 2023. "Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Peter Georgeson & Tabitha A. Harrison & Bernard J. Pope & Syed H. Zaidi & Conghui Qu & Robert S. Steinfelder & Yi Lin & Jihoon E. Joo & Khalid Mahmood & Mark Clendenning & Romy Walker & Efrat L. Amita, 2022. "Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Francesco Maura & David G. Coffey & Caleb K. Stein & Esteban Braggio & Bachisio Ziccheddu & Meaghen E. Sharik & Megan T. Du & Yuliza Tafoya Alvarado & Chang-Xin Shi & Yuan Xiao Zhu & Erin W. Meermeier, 2024. "The genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Johann-Christoph Jann & Maximilian Mossner & Vladimir Riabov & Eva Altrock & Nanni Schmitt & Johanna Flach & Qingyu Xu & Verena Nowak & Julia Obländer & Iris Palme & Nadine Weimer & Alexander Streuer , 2021. "Bone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    5. Manako Yamaguchi & Hirofumi Nakaoka & Kazuaki Suda & Kosuke Yoshihara & Tatsuya Ishiguro & Nozomi Yachida & Kyota Saito & Haruka Ueda & Kentaro Sugino & Yutaro Mori & Kaoru Yamawaki & Ryo Tamura & Sun, 2022. "Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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