Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing

被引：296

作者：

Rasche, L. ^{[1
]}

Chavan, S. S. ^{[1
]}

Stephens, O. W. ^{[1
]}

Patel, P. H. ^{[1
]}

Tytarenko, R. ^{[1
]}

Ashby, C. ^{[1
]}

Bauer, M. ^{[1
]}

Stein, C. ^{[1
]}

Deshpande, S. ^{[1
]}

Wardell, C. ^{[1
]}

Buzder, T. ^{[1
]}

Molnar, G. ^{[1
]}

Zangari, M. ^{[1
]}

van Rhee, F. ^{[1
]}

Thanendrarajan, S. ^{[1
]}

Schinke, C. ^{[1
]}

Epstein, J. ^{[1
]}

Davies, F. E. ^{[1
]}

Walker, B. A. ^{[1
]}

Meissner, T. ^{[2
]}

Barlogie, B. ^{[1
]}

Morgan, G. J. ^{[1
]}

Weinhold, N. ^{[1
]}

机构：

[1] Univ Arkansas Med Sci, Myeloma Inst, Little Rock, AR 72205 USA

[2] Avera Canc Inst, Dept Mol & Expt Med, Sioux Falls, SD 57105 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

INTERNATIONAL STAGING SYSTEM; POSITRON-EMISSION-TOMOGRAPHY; COPY NUMBER CHANGES; GENE-EXPRESSION; PLASMA-CELL; HIGH-RISK; CLONAL EVOLUTION; INTRATUMOR HETEROGENEITY; BIG-BANG; CANCER;

D O I：

10.1038/s41467-017-00296-y

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：

In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of "fitter" clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes. We show that the extent of spatial heterogeneity is positively associated with the size of biopsied focal lesions consistent with regional outgrowth of advanced clones. The results support a model for multiple myeloma progression with clonal sweeps in the early phase and regional evolution in advanced disease. We suggest that multi-region investigations are critical to understanding intra-patient heterogeneity and the evolutionary processes in multiple myeloma.

引用

页数：11

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