Genomic patterns of progression in smoldering multiple myeloma

Niccolò Bolli, Francesco Maura, Stephane Minvielle, Dominik Gloznik, Raphael Szalat, Anthony Fullam, Inigo Martincorena, Kevin J. Dawson, Mehmet Kemal Samur, Jorge Zamora, Patrick Tarpey, Helen Davies, Mariateresa Fulciniti, Masood A. Shammas, Yu Tzu Tai, Florence Magrangeas, Philippe Moreau, Paolo Corradini, Kenneth Anderson, Ludmil Alexandrov, David C. Wedge, Herve Avet-Loiseau (), Peter Campbell () and Nikhil Munshi ()
Additional contact information
Niccolò Bolli: University of Milan
Francesco Maura: University of Milan
Stephane Minvielle: Université de Nantes, Université d’Angers
Dominik Gloznik: Wellcome Trust Sanger Institute
Raphael Szalat: Harvard Medical School
Anthony Fullam: Wellcome Trust Sanger Institute
Inigo Martincorena: Wellcome Trust Sanger Institute
Kevin J. Dawson: Wellcome Trust Sanger Institute
Mehmet Kemal Samur: Harvard Medical School
Jorge Zamora: Wellcome Trust Sanger Institute
Patrick Tarpey: Wellcome Trust Sanger Institute
Helen Davies: Wellcome Trust Sanger Institute
Mariateresa Fulciniti: Harvard Medical School
Masood A. Shammas: Harvard Medical School
Yu Tzu Tai: Harvard Medical School
Florence Magrangeas: Université de Nantes, Université d’Angers
Philippe Moreau: Université de Nantes, Université d’Angers
Paolo Corradini: University of Milan
Kenneth Anderson: Harvard Medical School
Ludmil Alexandrov: University of California, San Diego
David C. Wedge: University of Oxford
Herve Avet-Loiseau: L’Institut Universitaire du Cancer Oncopole
Peter Campbell: University of Milan
Nikhil Munshi: Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract We analyzed whole genomes of unique paired samples from smoldering multiple myeloma (SMM) patients progressing to multiple myeloma (MM). We report that the genomic landscape, including mutational profile and structural rearrangements at the smoldering stage is very similar to MM. Paired sample analysis shows two different patterns of progression: a “static progression model”, where the subclonal architecture is retained as the disease progressed to MM suggesting that progression solely reflects the time needed to accumulate a sufficient disease burden; and a “spontaneous evolution model”, where a change in the subclonal composition is observed. We also observe that activation-induced cytidine deaminase plays a major role in shaping the mutational landscape of early subclinical phases, while progression is driven by APOBEC cytidine deaminases. These results provide a unique insight into myelomagenesis with potential implications for the definition of smoldering disease and timing of treatment initiation.

Date: 2018
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DOI: 10.1038/s41467-018-05058-y

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