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Abstract：
To provide insight into the subclonal architecture and co-dependency patterns of the alterations in Waldenström\'s macroglobulinemia (WM), we performed single-cell mutational and protein profiling of eight patients. A custom panel was designed to screen for mutations and copy number alterations at the single-cell level in samples taken from patients at diagnosis (n=5) or at disease progression (n=3). Results showed that in asymptomatic WM at diagnosis, MYD88L265P was the predominant clonal alteration; other events, if present, were secondary and subclonal to MYD88L265P. In symptomatic WM, clonal diversity was more evident, uncovering combinations of alterations that synergized to promote clonal expansion and dominance. At disease progression, a dominant clone was observed, sometimes accompanied by other less complex minor clones, which could be consistent with a clonal selection process. Clonal diversity was also reduced, probably due to the effect of treatment. Finally, we combined protein expression with mutational analysis to map somatic genotype with the immunophenotype. Our findings provide a comprehensive view of the clonality of tumor populations in WM and how clonal complexity can evolve and impact disease progression.
摘要：
为了深入了解Waldenström巨球蛋白血症（WM）改变的亚克隆结构和共同依赖模式，我们对8例患者进行了单细胞突变和蛋白质分析.设计定制组以在诊断时(n=5)或疾病进展时(n=3)在取自患者的样品中在单细胞水平上筛选突变和拷贝数改变。结果显示，在诊断时无症状的WM中，MYD88L265P是主要的克隆变异，而其他事件,如果存在，是MYD88L265P的继发性亚克隆。在有症状的WM中，克隆多样性更加明显，发现协同促进克隆扩张和优势的改变组合。在疾病进展时，观察到一个显性克隆，有时伴随着其他不太复杂的次要克隆，这可能与克隆选择过程一致。克隆多样性也减少了，可能是由于治疗的效果。最后,我们将蛋白质表达与突变分析相结合，以绘制体细胞基因型和免疫表型。我们的发现提供了WM中肿瘤群体的克隆性以及克隆复杂性如何进化和影响疾病进展的全面视图。
