Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour.

中文翻译：

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独特的遗传变化揭示了具有MYC / BCL2双重打击的DLBCL的进化历史和异质分子等级。

使用Burkitt样淋巴瘤样基因表达特征，我们最近定义了一个高风险分子高级别（MHG）组，主要位于生发中心B细胞内，如弥漫性大B细胞淋巴瘤（GCB-DLBCL），其中富含MYC / BCL2双击（MYC / BCL2-DH）。MHG-DLBCL的遗传基础及其侵略性临床行为仍然未知。我们通过靶向测序和基因表达谱分析调查了697例DLBCL病例，特别是那些MYC / BCL2-DH（n = 62）的病例。我们显示，具有MYC / BCL2-DH的DLBCL和具有BCL2易位的DLBCL具有与滤泡性淋巴瘤及其高度转化有关的特征性突变特征。我们确定了频繁的MYC热点突变，这些突变会影响磷酸化位点（T58）及其相邻氨基酸，这对于MYC蛋白降解很重要。这些MYC突变在部分MYC易位病例中可见，但主要发生在MHG突变中。在以IG为MYC易位伴侣的重击淋巴瘤中，突变更为频繁，并且与MYC蛋白表达较高和患者生存期较差有关。具有MYC / BCL2-DH的DLBCL和仅具有BCL2易位的DLBCL最有可能源自滤泡性淋巴瘤或其前体病变，并且获得MYC致病性突变可能会增强MYC功能，从而导致侵略性临床行为。并与更高的MYC蛋白表达和较差的患者生存率相关。具有MYC / BCL2-DH的DLBCL和仅具有BCL2易位的DLBCL最有可能源自滤泡性淋巴瘤或其前体病变，并且获得MYC致病性突变可能会增强MYC功能，从而导致侵略性临床行为。并与更高的MYC蛋白表达和较差的患者生存率相关。具有MYC / BCL2-DH的DLBCL和仅具有BCL2易位的DLBCL最有可能源自滤泡性淋巴瘤或其前体病变，并且获得MYC致病性突变可能会增强MYC功能，从而导致侵略性临床行为。