Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

Niccolo Bolli, Hervé Avet-Loiseau, David C. Wedge, Peter Van Loo, Ludmil B. Alexandrov, Inigo Martincorena, Kevin J. Dawson, Francesco Iorio, Serena Nik-Zainal, Graham R. Bignell, Jonathan W. Hinton, Yilong Li, Jose M.C. Tubio, Stuart McLaren, Sarah O' Meara, Adam P. Butler, Jon W. Teague, Laura Mudie, Elizabeth Anderson, Naim Rashid, Yu-Tzu Tai, Masood A. Shammas, Adam S. Sperling, Mariateresa Fulciniti, Paul G. Richardson, Giovanni Parmigiani, Florence Magrangeas, Stephane Minvielle, Philippe Moreau, Michel Attal, Thierry Facon, P Andrew Futreal, Kenneth C. Anderson, Peter J. Campbell () and Nikhil C. Munshi ()
Additional contact information
Niccolo Bolli: Cancer Genome Project, Wellcome Trust Sanger Institute
Hervé Avet-Loiseau: Unité de Génomique du Myélome, CHU Rangueil
David C. Wedge: Cancer Genome Project, Wellcome Trust Sanger Institute
Peter Van Loo: Cancer Genome Project, Wellcome Trust Sanger Institute
Ludmil B. Alexandrov: Cancer Genome Project, Wellcome Trust Sanger Institute
Inigo Martincorena: Cancer Genome Project, Wellcome Trust Sanger Institute
Kevin J. Dawson: Cancer Genome Project, Wellcome Trust Sanger Institute
Francesco Iorio: Cancer Genome Project, Wellcome Trust Sanger Institute
Serena Nik-Zainal: Cancer Genome Project, Wellcome Trust Sanger Institute
Graham R. Bignell: Cancer Genome Project, Wellcome Trust Sanger Institute
Jonathan W. Hinton: Cancer Genome Project, Wellcome Trust Sanger Institute
Yilong Li: Cancer Genome Project, Wellcome Trust Sanger Institute
Jose M.C. Tubio: Cancer Genome Project, Wellcome Trust Sanger Institute
Stuart McLaren: Cancer Genome Project, Wellcome Trust Sanger Institute
Sarah O' Meara: Cancer Genome Project, Wellcome Trust Sanger Institute
Adam P. Butler: Cancer Genome Project, Wellcome Trust Sanger Institute
Jon W. Teague: Cancer Genome Project, Wellcome Trust Sanger Institute
Laura Mudie: Cancer Genome Project, Wellcome Trust Sanger Institute
Elizabeth Anderson: Cancer Genome Project, Wellcome Trust Sanger Institute
Naim Rashid: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School
Yu-Tzu Tai: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School
Masood A. Shammas: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School
Adam S. Sperling: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School
Mariateresa Fulciniti: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School
Paul G. Richardson: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School
Giovanni Parmigiani: Dana–Farber Cancer Institute and Harvard School of Public Health
Florence Magrangeas: Center for Cancer Research Nantes-Angers, UMR 892 Inserm-6299 CNRS-University of Nantes
Stephane Minvielle: Center for Cancer Research Nantes-Angers, UMR 892 Inserm-6299 CNRS-University of Nantes
Philippe Moreau: University Hospital
Michel Attal: University Hospital and CRCT, INSERM U1037
Thierry Facon: University Hospital
P Andrew Futreal: Cancer Genome Project, Wellcome Trust Sanger Institute
Kenneth C. Anderson: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School
Peter J. Campbell: Cancer Genome Project, Wellcome Trust Sanger Institute
Nikhil C. Munshi: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.

Date: 2014
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DOI: 10.1038/ncomms3997

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