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

L. Rasche; S. S. Chavan; O. W. Stephens; P. H. Patel; R. Tytarenko; C. Ashby; M. Bauer; C. Stein; S. Deshpande; C. Wardell; T. Buzder; G. Molnar; M. Zangari; F. Van Rhee; S. Thanendrarajan; C. Schinke; J. Epstein; F. E. Davies; B. A. Walker; T. Meissner; B. Barlogie; G. J. Morgan; N. Weinhold

doi:10.1038/s41467-017-00296-y

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

L. Rasche
, S. S. Chavan
, O. W. Stephens
, P. H. Patel
, R. Tytarenko
, C. Ashby
, M. Bauer
, C. Stein
, S. Deshpande
, C. Wardell
, T. Buzder
, G. Molnar
, M. Zangari
, F. Van Rhee
, S. Thanendrarajan
, C. Schinke
, J. Epstein
, F. E. Davies
, B. A. Walker
, T. Meissner

B. Barlogie, G. J. Morgan, N. Weinhold

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

337 Scopus citations

Abstract

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.

Original language	English
Article number	268
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00296-y
State	Published - 1 Dec 2017
Externally published	Yes

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Rasche, L., Chavan, S. S., Stephens, O. W., Patel, P. H., Tytarenko, R., Ashby, C., Bauer, M., Stein, C., Deshpande, S., Wardell, C., Buzder, T., Molnar, G., Zangari, M., Van Rhee, F., Thanendrarajan, S., Schinke, C., Epstein, J., Davies, F. E., Walker, B. A., ... Weinhold, N. (2017). Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nature Communications, 8(1), Article 268. https://doi.org/10.1038/s41467-017-00296-y

@article{cbef8dbaa6e0424caccdd63100e41ad4,

title = "Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing",

abstract = "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.",

author = "L. Rasche and Chavan, \{S. S.\} and Stephens, \{O. W.\} and Patel, \{P. H.\} and R. Tytarenko and C. Ashby and M. Bauer and C. Stein and S. Deshpande and C. Wardell and T. Buzder and G. Molnar and M. Zangari and \{Van Rhee\}, F. and S. Thanendrarajan and C. Schinke and J. Epstein and Davies, \{F. E.\} and Walker, \{B. A.\} and T. Meissner and B. Barlogie and Morgan, \{G. J.\} and N. Weinhold",

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year = "2017",

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doi = "10.1038/s41467-017-00296-y",

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Rasche, L, Chavan, SS, Stephens, OW, Patel, PH, Tytarenko, R, Ashby, C, Bauer, M, Stein, C, Deshpande, S, Wardell, C, Buzder, T, Molnar, G, Zangari, M, Van Rhee, F, Thanendrarajan, S, Schinke, C, Epstein, J, Davies, FE, Walker, BA, Meissner, T, Barlogie, B, Morgan, GJ & Weinhold, N 2017, 'Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing', Nature Communications, vol. 8, no. 1, 268. https://doi.org/10.1038/s41467-017-00296-y

TY - JOUR

T1 - Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing

AU - Rasche, L.

AU - Chavan, S. S.

AU - Stephens, O. W.

AU - Patel, P. H.

AU - Tytarenko, R.

AU - Ashby, C.

AU - Bauer, M.

AU - Stein, C.

AU - Deshpande, S.

AU - Wardell, C.

AU - Buzder, T.

AU - Molnar, G.

AU - Zangari, M.

AU - Van Rhee, F.

AU - Thanendrarajan, S.

AU - Schinke, C.

AU - Epstein, J.

AU - Davies, F. E.

AU - Walker, B. A.

AU - Meissner, T.

AU - Barlogie, B.

AU - Morgan, G. J.

AU - Weinhold, N.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85027511213

U2 - 10.1038/s41467-017-00296-y

DO - 10.1038/s41467-017-00296-y

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C2 - 28814763

AN - SCOPUS:85027511213

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 268

ER -

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

Abstract

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