Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
Haematologica. 2017 Sep;102(9):1617-1625. doi: 10.3324/haematol.2017.163766. Epub 2017 May 26.
Monoclonal gammopathy of undetermined significance is a pre-malignant precursor of multiple myeloma with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as translocations, deletion, 1q gain, hyperdiploidy or RAS gene mutations, little is known about the molecular mechanism of malignant transformation. We performed whole exome sequencing together with comparative genomic hybridization plus single nucleotide polymorphism array analysis in 33 flow-cytometry-separated abnormal plasma cell samples from patients with monoclonal gammopathy of undetermined significance to describe somatic gene mutations and chromosome changes at the genome-wide level. Non-synonymous mutations and copy-number alterations were present in 97.0% and in 60.6% of cases, respectively. Importantly, the number of somatic mutations was significantly lower in monoclonal gammopathy of undetermined significance than in myeloma (<10) and we identified six genes that were significantly mutated in myeloma (, , , , and ) within the monoclonal gammopathy of undetermined significance dataset. We also found a positive correlation with increasing chromosome changes and somatic gene mutations. translocations, comprising t(4;14), t(11;14), t(14;16) and t(14;20), were present in 27.3% of cases and in a similar frequency to myeloma, consistent with the primary lesion hypothesis. translocations and deletions or mutations were not detected in samples from patients with monoclonal gammopathy of undetermined significance, indicating that they may be drivers of progression to myeloma. Data from this study show that monoclonal gammopathy of undetermined significance is genetically similar to myeloma, however overall genetic abnormalities are present at significantly lower levels in monoclonal gammopathy of undetermined significant than in myeloma.
意义未明的单克隆丙种球蛋白血症是多发性骨髓瘤的恶性前体，每年有 1%的进展风险。虽然靶向分析显示存在特定的遗传异常，如易位、缺失、1q 增益、超二倍体或 RAS 基因突变，但恶性转化的分子机制知之甚少。我们对 33 例意义未明的单克隆丙种球蛋白血症患者的流式细胞术分离的异常浆细胞样本进行了全外显子组测序以及比较基因组杂交加单核苷酸多态性微阵列分析，以描述全基因组水平的体细胞基因突变和染色体变化。非同义突变和拷贝数改变分别存在于 97.0%和 60.6%的病例中。重要的是，意义未明的单克隆丙种球蛋白血症中的体细胞突变数量明显低于骨髓瘤（<10），并且我们在意义未明的单克隆丙种球蛋白血症数据集中鉴定出了 6 个在骨髓瘤中显著突变的基因（、、、、和）。我们还发现染色体改变和体细胞基因突变之间存在正相关。包含 t(4;14)、t(11;14)、t(14;16)和 t(14;20)的易位在 27.3%的病例中存在，与骨髓瘤的频率相似，符合原发性病变假说。意义未明的单克隆丙种球蛋白血症样本中未检测到 t(14;16)和 t(14;20)易位以及 缺失或突变，表明它们可能是进展为骨髓瘤的驱动因素。本研究数据表明，意义未明的单克隆丙种球蛋白血症在遗传学上与骨髓瘤相似，然而，意义未明的单克隆丙种球蛋白血症中的总体遗传异常水平明显低于骨髓瘤。
