Genomic patterns of progression in smoldering multiple myeloma

Niccolò Bolli 1, 2, 3 Francesco Maura 1 Stephane Minvielle 4 Dominik Gloznik 3 Raphael Szalat 5 Anthony Fullam 3 Inigo Martincorena 3 Kevin Dawson 3 Mehmet Samur 5 Jorge Zamora 3 Patrick Tarpey 3 Helen Davies 3 Mariateresa Fulciniti 5 Masood Shammas 5 Yu-Tzu Tai 5 Florence Magrangeas 4 Philippe Moreau 4 Paolo Corradini 1, 2 Kenneth Anderson 5 Ludmil Alexandrov 6 David Wedge 7 Hervé Avet-Loiseau 8, * Peter Campbell 1, * Nikhil Munshi 5, 9, *
* Corresponding author
1 Department of Oncology and Hemato-Oncology [Milan, Italy]
2 Fondazione IRCCS - Department of Oncology and Hematology [Milan, Italy]
3 Cancer Genome Project [Cambridgeshire, UK]
4 CRCINA - Département NOHMAD - Equipe 11 - Integrative oncogenomics of multiple myeloma pathogenesis and progression
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
5 Jerome Lipper Multiple Myeloma Center [Boston, MA, USA]
6 Moores Cancer Center - Dept of Cellular and Molecular Medicine and Dept of Bioengineering [San Diego, La Jolla, CA, USA]
7 Big Data Institute - Nuffield Department of Medicine [Oxford, UK]
8 Laboratoire de génomique du myélome [IUCT Oncopole, Toulouse]
9 VA Boston Healthcare System
Abstract : We analyzed whole genomes of unique paired samples from smoldering multiple mye-loma (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 dea-minase 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.
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Niccolò Bolli, Francesco Maura, Stephane Minvielle, Dominik Gloznik, Raphael Szalat, et al.. Genomic patterns of progression in smoldering multiple myeloma. Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.3363. ⟨10.1038/s41467-018-05058-y⟩. ⟨inserm-01885513⟩

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