Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, C1425AUM, Argentina.
Divisão De Hematologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, 14048-900, Brazil.
Am J Hematol. 2016 May;91(5):481-5. doi: 10.1002/ajh.24324. Epub 2016 Apr 4.
Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with poor prognosis. Acquired telomerase reverse transcriptase gene promoter (TERTp) mutations are among the most frequent somatic non-coding mutations in cancers. In this study, the prevalence of TERTp mutations in 24 MCL and 21 other lymphoid neoplasias (oLN) was investigated. Eight MCL samples (33%) carried TERTp mutations, two homozygous and six heterozygous (seven C228T and one C250T), which directly correlated with higher TERT transcription, mitochondrial DNA copy number, and IGHV mutational status in MCL neoplastic cells. TERTp mutations were not found in oLN. TERTp mutations correlated with more lymphoma proliferation and tumor burden, as suggested by the higher number of lymphoma cells circulating in peripheral blood, and tended to associate with longer MCL telomeres, especially in homozygous mutants, although not statistically significant. Telomere-biology genes were overexpressed in MCL cells in comparison to healthy lymphocytes, but were not influenced by mutation status. The findings described for the first time that acquired TERTp mutations are common in MCL but not in other lymphoid neoplasms. It was also demonstrated that TERTp mutations are associated with higher TERT mRNA expression in MCL cells in vivo and higher tumor burden, suggesting these mutations as a driver event in MCL development and progression.
套细胞淋巴瘤（MCL）是一种侵袭性淋巴肿瘤，预后不良。获得性端粒酶逆转录酶基因启动子（TERTp）突变是癌症中最常见的体细胞非编码突变之一。在这项研究中，调查了 24 例 MCL 和 21 例其他淋巴肿瘤（oLN）中 TERTp 突变的发生率。8 例 MCL 样本（33%）携带 TERTp 突变，其中 2 例为纯合突变，6 例为杂合突变（7 例为 C228T，1 例为 C250T），这与 MCL 肿瘤细胞中更高的 TERT 转录、线粒体 DNA 拷贝数和 IGHV 突变状态直接相关。oLN 中未发现 TERTp 突变。TERTp 突变与更多的淋巴瘤增殖和肿瘤负担相关，这表现为外周血中循环的淋巴瘤细胞数量更多，并且倾向于与更长的 MCL 端粒相关，尤其是在纯合突变体中，尽管这没有统计学意义。与健康淋巴细胞相比，MCL 细胞中端粒生物学基因表达上调，但不受突变状态影响。这些发现首次表明，获得性 TERTp 突变在 MCL 中很常见，但在其他淋巴肿瘤中不存在。此外，还证明了 TERTp 突变与 MCL 细胞中更高的 TERT mRNA 表达和更高的肿瘤负担相关，提示这些突变是 MCL 发生和进展的驱动事件。
