33 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS)

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor of multiple myeloma (MM) with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS genes mutations, little is known about molecular mechanism of malignant transformation. We have performed whole exome sequencing together with SNP array analysis in 33 flow-cytometry separated abnormal PC samples of MGUS patients to describe somatic gene mutations and chromosome changes at the genome-wide level. Non-synonymous mutations (NS-SNVs) and copy number alterations (CNAs) were present in 97.0% and in 63.6% of cases, respectively. Importantly, the number of somatic mutations was significantly lower in MGUS compared to MM (p<10-4) and we have identified 6 myeloma significantly mutated genes which are KRAS, NRAS, DIS3, HIST1H1E, EGR1 and LTB in the MGUS dataset. We also found a positive correlation with increasing chromosome changes and somatic mutations. IGH translocations were present in 27.3% of cases comprising t(4;14), t(11;14), t(14;16) or t(14;20) and were in a similar frequency to MM, which corresponded with primary lesion hypothesis. Data from this study showed MGUS is a genetically comprehensive disease, however overall genetic instability is significantly lower compared to MM.

意义未定的单克隆 gammopathy（MGUS）是多发性骨髓瘤（MM）的癌前病变，每年进展风险为1%。尽管靶向分析已显示出诸如IGH转位、RB1缺失、1q扩增、超二倍体或RAS基因突变等特定的遗传异常的存在，但对于恶性转化的分子机制了解甚少。我们对MGUS患者的33例流式细胞术分离的异常PC样本进行了全外显子测序以及单核苷酸多态性（SNP）阵列分析，以描述基因组水平上的体细胞基因突变和染色体变化。在97.0%的案例中存在非同义突变（NS-SNVs），在63.6%的案例中存在拷贝数变异（CNAs）。值得注意的是，与MM相比，MGUS中的体细胞突变数量显著较低（p<10^-4），我们在MGUS数据集中识别了6个显著突变的骨髓瘤基因，分别为KRAS、NRAS、DIS3、HIST1H1E、EGR1和LTB。我们还发现染色体变化和体细胞突变之间存在正相关。27.3%的案例中存在IGH转位，包括t(4;14)、t(11;14)、t(14;16)或t(14;20)，其频率与MM相似，这与原发灶假说相吻合。本研究数据表明，MGUS是一种遗传上复杂的疾病，然而，与MM相比，其整体遗传不稳定性显著较低。