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; Nikhil C. Munshi

doi:10.1038/ncomms3997

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 RashidYu 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, Nikhil C. Munshi

Genomic Medicine

Research output: Contribution to journal › Article › peer-review

687 Scopus citations

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.

Original language	English (US)
Article number	2997
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms3997
State	Published - Jan 16 2014

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Bolli, N., Avet-Loiseau, H., Wedge, D. C., Van Loo, P., Alexandrov, L. B., Martincorena, I., Dawson, K. J., Iorio, F., Nik-Zainal, S., Bignell, G. R., Hinton, J. W., Li, Y., Tubio, J. M. C., McLaren, S., O'Meara, S., Butler, A. P., Teague, J. W., Mudie, L., Anderson, E., ... Munshi, N. C. (2014). Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nature communications, 5, Article 2997. https://doi.org/10.1038/ncomms3997

Bolli, N, Avet-Loiseau, H, Wedge, DC, Van Loo, P, Alexandrov, LB, Martincorena, I, Dawson, KJ, Iorio, F, Nik-Zainal, S, Bignell, GR, Hinton, JW, Li, Y, Tubio, JMC, McLaren, S, O'Meara, S, Butler, AP, Teague, JW, Mudie, L, Anderson, E, Rashid, N, Tai, YT, Shammas, MA, Sperling, AS, Fulciniti, M, Richardson, PG, Parmigiani, G, Magrangeas, F, Minvielle, S, Moreau, P, Attal, M, Facon, T, Futreal, PA, Anderson, KC, Campbell, PJ & Munshi, NC 2014, 'Heterogeneity of genomic evolution and mutational profiles in multiple myeloma', Nature communications, vol. 5, 2997. https://doi.org/10.1038/ncomms3997

@article{36ae11e201c348ae9ce0906b5f19d4b5,

title = "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.",

author = "Niccolo Bolli and Herv{\'e} Avet-Loiseau and Wedge, {David C.} and {Van Loo}, Peter and Alexandrov, {Ludmil B.} and Inigo Martincorena and Dawson, {Kevin J.} and Francesco Iorio and Serena Nik-Zainal and Bignell, {Graham R.} and Hinton, {Jonathan W.} and Yilong Li and Tubio, {Jose M.C.} and Stuart McLaren and Sarah O'Meara and Butler, {Adam P.} and Teague, {Jon W.} and Laura Mudie and Elizabeth Anderson and Naim Rashid and Tai, {Yu Tzu} and Shammas, {Masood A.} and Sperling, {Adam S.} and Mariateresa Fulciniti and Richardson, {Paul G.} and Giovanni Parmigiani and Florence Magrangeas and Stephane Minvielle and Philippe Moreau and Michel Attal and Thierry Facon and Futreal, {P. Andrew} and Anderson, {Kenneth C.} and Campbell, {Peter J.} and Munshi, {Nikhil C.}",

note = "Funding Information: This work was supported by a grant from NIH PO1-155258 (N.C.M., P.J.C., K.C.A., H.A.-L. and S.M.), RO1-124929 (N.C.M.) P50-100007 (K.C.A. and N.C.M.) PO1-78378 (K.C.A. and N.C.M.) NIH RCA125711C (M.A.S.), by a Veterans Administration grant I01--BX001584 (N.C.M.), and by the Wellcome Trust (grant reference 077012/Z/05/Z). P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship. K.C.A. is an American Cancer Society Clinical Research Professor N.B. is an EHA fellow and has been supported by a grant from the Lady Tata Memorial Trust. P.V.L. is a postdoctoral researcher of the Research Foundation-Flanders. S.N.-Z. is funded through a Wellcome Trust Intermediate Clinical Fellowship. We thank the Intergroupe Francophone du Myelome for providing patient samples and scientific support.",

year = "2014",

month = jan,

day = "16",

doi = "10.1038/ncomms3997",

language = "English (US)",

volume = "5",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

AU - Bolli, Niccolo

AU - Avet-Loiseau, Hervé

AU - Wedge, David C.

AU - Van Loo, Peter

AU - Alexandrov, Ludmil B.

AU - Martincorena, Inigo

AU - Dawson, Kevin J.

AU - Iorio, Francesco

AU - Nik-Zainal, Serena

AU - Bignell, Graham R.

AU - Hinton, Jonathan W.

AU - Li, Yilong

AU - Tubio, Jose M.C.

AU - McLaren, Stuart

AU - O'Meara, Sarah

AU - Butler, Adam P.

AU - Teague, Jon W.

AU - Mudie, Laura

AU - Anderson, Elizabeth

AU - Rashid, Naim

AU - Tai, Yu Tzu

AU - Shammas, Masood A.

AU - Sperling, Adam S.

AU - Fulciniti, Mariateresa

AU - Richardson, Paul G.

AU - Parmigiani, Giovanni

AU - Magrangeas, Florence

AU - Minvielle, Stephane

AU - Moreau, Philippe

AU - Attal, Michel

AU - Facon, Thierry

AU - Futreal, P. Andrew

AU - Anderson, Kenneth C.

AU - Campbell, Peter J.

AU - Munshi, Nikhil C.

N1 - Funding Information: This work was supported by a grant from NIH PO1-155258 (N.C.M., P.J.C., K.C.A., H.A.-L. and S.M.), RO1-124929 (N.C.M.) P50-100007 (K.C.A. and N.C.M.) PO1-78378 (K.C.A. and N.C.M.) NIH RCA125711C (M.A.S.), by a Veterans Administration grant I01--BX001584 (N.C.M.), and by the Wellcome Trust (grant reference 077012/Z/05/Z). P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship. K.C.A. is an American Cancer Society Clinical Research Professor N.B. is an EHA fellow and has been supported by a grant from the Lady Tata Memorial Trust. P.V.L. is a postdoctoral researcher of the Research Foundation-Flanders. S.N.-Z. is funded through a Wellcome Trust Intermediate Clinical Fellowship. We thank the Intergroupe Francophone du Myelome for providing patient samples and scientific support.

PY - 2014/1/16

Y1 - 2014/1/16

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms3997

DO - 10.1038/ncomms3997

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VL - 5

JO - Nature communications

JF - Nature communications

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ER -

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

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