Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

被引：693

作者：

Bolli, Niccolo ^{[1
,2
]}

Avet-Loiseau, Herve ^{[3
,4
]}

Wedge, David C. ^{[1
]}

Van Loo, Peter ^{[1
,5
,6
]}

Alexandrov, Ludmil B. ^{[1
]}

Martincorena, Inigo ^{[1
]}

Dawson, Kevin J. ^{[1
]}

Iorio, Francesco ^{[1
,7
]}

Nik-Zainal, Serena ^{[1
,8
]}

Bignell, Graham R. ^{[1
]}

Hinton, Jonathan W. ^{[1
]}

Li, Yilong ^{[1
]}

Tubio, Jose M. C. ^{[1
]}

McLaren, Stuart ^{[1
]}

Meara, Sarah O' ^{[1
]}

Butler, Adam P. ^{[1
]}

Teague, Jon W. ^{[1
]}

Mudie, Laura ^{[1
]}

Anderson, Elizabeth ^{[1
]}

Rashid, Naim ^{[9
,10
]}

Tai, Yu-Tzu ^{[9
,10
]}

Shammas, Masood A. ^{[9
,10
,11
]}

Sperling, Adam S. ^{[9
,10
]}

Fulciniti, Mariateresa ^{[9
,10
]}

Richardson, Paul G. ^{[9
,10
]}

Parmigiani, Giovanni ^{[12
,13
]}

Magrangeas, Florence ^{[14
,15
]}

Minvielle, Stephane ^{[14
,15
]}

Moreau, Philippe ^{[16
]}

Attal, Michel ^{[17
,18
]}

Facon, Thierry ^{[19
]}

Futreal, P. Andrew ^{[1
]}

Anderson, Kenneth C. ^{[9
,10
]}

Campbell, Peter J. ^{[1
,2
]}

Munshi, Nikhil C. ^{[9
,10
,11
]}

机构：

[1] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England

[2] Univ Cambridge, CIMR, Dept Haematol, Cambridge CB2 0XY, England

[3] CHU Rangueil, Unite Genom Myelome, F-31059 Toulouse, France

[4] INSERM, U1037, CRCT, F-31400 Toulouse, France

[5] VIB, Dept Human Genet, B-3000 Louvain, Belgium

[6] Univ Leuven, B-3000 Louvain, Belgium

[7] European Bioinformat Inst, European Mol Biol Lab, Hinxton CB10 1SA, England

[8] Addenbrookes Hosp NHS Trust, Dept Med Genet, Cambridge CB2 0QQ, England

[9] Harvard Univ, Sch Med, Lebow Inst Myeloma Therapeut, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA

[11] Boston Vet Adm Healthcare Syst, West Roxbury, MA 02132 USA

[12] Dana Farber Canc Inst, Boston, MA 02115 USA

[13] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA

[14] Univ Nantes, IRS UN, Inserm CNRS 6299, Ctr Canc Res Nantes Angers,UMR 892, F-44072 Nantes, France

[15] Univ Hosp, UMGC, F-44093 Nantes, France

[16] Univ Hosp, Dept Hematol, F-44093 Nantes, France

[17] Univ Hosp, Dept Hematol, F-31400 Toulouse, France

[18] INSERM, CRCT, U1037, F-31400 Toulouse, France

[19] Univ Hosp, Dept Hematol, F-59045 Lille, France

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

基金：

英国惠康基金;

关键词：

KAPPA-B PATHWAY; INTRACLONAL HETEROGENEITY; SOMATIC MUTATIONS; FREQUENT MUTATION; CANCER; ACTIVATION; PROTEIN; FAMILY; GENES; CLASSIFICATION;

D O I：

10.1038/ncomms3997

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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