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.
Highlights
In multiple myeloma malignant plasma cells expand within the bone marrow
MM is a interesting model system to gain insights into the molecular progression in cancer because its mutational load falls in the middle of the range of mutations seen in cancer lying somewhere between a genetically complex solid malignancy constrained in its evolution by neighboring cells and the genetically simple leukemia, which is distributed throughout the bone marrow (BM) with less anatomical constraints[2]
Genomic heterogeneity can be deciphered through the analysis of numerical or structural chromosomal aberrations, short insertions or deletions (Indels) or single nucleotide variants (SNVs), and we describe heterogeneity at all of these levels
Summary
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. Molecular data available to date have been interpreted in the context of a disease model where MM is the end result of a multistep transformation process during which the acquisition of genetic hits leads to the generation of branching evolutionary pathways[2, 4] According to this Darwinian model, the acquisition of sequential mutations results in better adaptation of clonal cells to their microenvironment leading to the outgrowth of “fitter” clones, which outcompete previously dominant clones[2]. MM primarily grows in the BM, where free movement between sites through the circulation is assumed, a feature consistent with small numbers of clonal cells being seen in the peripheral blood using flow cytometry[5, 6] Based on this observation and in contrast to solid cancers[7, 8], a rapid and homogenous dissemination of “fitter” clones throughout the BMcontaining skeletal system may be anticipated.
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