Dataset Information

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

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.

SUBMITTER: Bolli N

PROVIDER: S-EPMC3905727 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

Bolli Niccolo N Avet-Loiseau Hervé H Wedge David C DC Van Loo Peter P Alexandrov Ludmil B LB Martincorena Inigo I Dawson Kevin J KJ Iorio Francesco F Nik-Zainal Serena S Bignell Graham R GR Hinton Jonathan W JW Li Yilong Y Tubio Jose M C JM McLaren Stuart S O' Meara Sarah S Butler Adam P AP Teague Jon W JW Mudie Laura L Anderson Elizabeth E Rashid Naim N Tai Yu-Tzu YT Shammas Masood A MA Sperling Adam S AS Fulciniti Mariateresa M Richardson Paul G PG Parmigiani Giovanni G Magrangeas Florence F Minvielle Stephane S Moreau Philippe P Attal Michel M Facon Thierry T Futreal P Andrew PA Anderson Kenneth C KC Campbell Peter J PJ Munshi Nikhil C NC

Nature communications 20140101

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. Di ...[more]

PMID: 24429703

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Project description:Multiple Myeloma (MM) arises from malignant transformation and deregulated proliferation of clonal plasma cells (PCs) harbouring heterogeneous molecular anomalies. The effect of evolving mutations on clone fitness and their cellular prevalence shapes the progressing myeloma genome and impacts clinical outcomes. Although clonal heterogeneity in MM is well established, which subclonal mutations emerge/persist/perish with progression in MM and which of these can be targeted therapeutically remains an open question. In line with this, we have sequenced pairwise whole exomes of 62 MM patients collected at two time points, i.e., at diagnosis and on progression. Somatic variants were called using a novel ensemble approach where a consensus was deduced from four variant callers (Illumina's Dragen, Strelka2, SomaticSniper and SpeedSeq) and actionable/druggable gene targets were identified. A marked intraclonal heterogeneity was observed. Branching evolution was observed among 72.58% patients, of whom 64.51% had low TMBs (<10) and 61.29% had 2 or more founder clones. The hypermutator patients (with high TMB levels ≥10 to ≤100) showed a significant decrease in their TMBs from diagnosis (median TMB 77.11) to progression (median TMB 31.22). A distinct temporal fall in subclonal driver mutations was identified recurrently across diagnosis to progression e.g., in PABPC1, BRAF, KRAS, CR1, DIS3 and ATM genes in 3 or more patients suggesting such patients could be treated early with target specific drugs like Vemurafenib/Cobimetinib. An analogous rise in driver mutations was observed in KMT2C, FOXD4L1, SP140, NRAS and other genes. A few drivers such as FAT4, IGLL5 and CDKN1A retained consistent distribution patterns at two time points. These findings are clinically relevant and point at consideration of evaluating multi time point subclonal mutational landscapes for designing better risk stratification strategies and tailoring time to time risk adapted combination therapies in future.

Dataset Information

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

Publications

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

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