Behboudi Afrouz, Enlund Fredrik, Winnes Marta, Andrén Ywonne, Nordkvist Anders, Leivo Ilmo, Flaberg Emilie, Szekely Laszlo, Mäkitie Antti, Grenman Reidar, Mark Joachim, Stenman Göran
Lundberg Laboratory for Cancer Research, Department of Pathology, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
Genes Chromosomes Cancer. 2006 May;45(5):470-81. doi: 10.1002/gcc.20306.
Mucoepidermoid carcinomas (MECs) of the salivary and bronchial glands are characterized by a recurrent t(11;19)(q21;p13) translocation resulting in a MECT1-MAML2 fusion in which the CREB-binding domain of the CREB coactivator MECT1 (also known as CRTC1, TORC1 or WAMTP1) is fused to the transactivation domain of the Notch coactivator MAML2. To gain further insights into the molecular pathogenesis of MECs, we cytogenetically and molecularly characterized a series of 29 MECs. A t(11;19) and/or an MECT1-MAML2 fusion was detected in more than 55% of the tumors. Several cases with cryptic rearrangements that resulted in gene fusions were detected. In fusion-negative MECs, the most common aberration was a single or multiple trisomies. Western blot and immunohistochemical studies demonstrated that the MECT1-MAML2 fusion protein was expressed in all MEC-specific cell types. In addition, cotransfection experiments showed that the fusion protein colocalized with CREB in homogeneously distributed nuclear granules. Analyses of potential downstream targets of the fusion revealed differential expression of the cAMP/CREB (FLT1 and NR4A2) and Notch (HES1 and HES5) target genes in fusion-positive and fusion-negative MECs. Moreover, clinical follow-up studies revealed that fusion-positive patients had a significantly lower risk of local recurrence, metastases, or tumor-related death compared to fusion-negative patients (P = 0.0012). When considering tumor-related deaths only, the estimated median survival for fusion-positive patients was greater than 10 years compared to 1.6 years for fusion-negative patients. These findings suggest that molecularly classifying MECs on the basis of an MECT1-MAML2 fusion is histopathologically and clinically relevant and that the fusion is a useful marker in predicting the biological behavior of MECs.
唾液腺和支气管黏液表皮样癌（MEC）的特征是存在复发性t(11;19)(q21;p13)易位，导致MECT1-MAML2融合，其中CREB共激活因子MECT1（也称为CRTC1、TORC1或WAMTP1）的CREB结合结构域与Notch共激活因子MAML2的反式激活结构域融合。为了进一步深入了解MEC的分子发病机制，我们对一系列29例MEC进行了细胞遗传学和分子特征分析。超过55%的肿瘤中检测到t(11;19)和/或MECT1-MAML2融合。检测到几例导致基因融合的隐匿性重排病例。在融合阴性的MEC中，最常见的异常是单条或多条染色体三体。蛋白质印迹和免疫组织化学研究表明，MECT1-MAML2融合蛋白在所有MEC特异性细胞类型中均有表达。此外，共转染实验表明，融合蛋白与CREB在均匀分布的核颗粒中共定位。对融合潜在下游靶点的分析显示，cAMP/CREB（FLT1和NR4A2）和Notch（HES1和HES5）靶点基因在融合阳性和融合阴性MEC中存在差异表达。此外，临床随访研究表明，与融合阴性患者相比，融合阳性患者局部复发、转移或肿瘤相关死亡的风险显著降低（P = 0.0012）。仅考虑肿瘤相关死亡时，融合阳性患者的估计中位生存期大于10年，而融合阴性患者为1.6年。这些发现表明，基于MECT1-MAML2融合对MEC进行分子分类在组织病理学和临床上具有相关性，并且该融合是预测MEC生物学行为的有用标志物。
