Molecular classification of mucoepidermoid carcinomas—Prognostic significance of the MECT1–MAML2 fusion oncogene
- 27 January 2006
- journal article
- research article
- Published by Wiley in Genes, Chromosomes and Cancer
- Vol. 45 (5), 470-481
- https://doi.org/10.1002/gcc.20306
Abstract
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.Keywords
This publication has 26 references indexed in Scilit:
- Mect1-Maml2 Fusion Oncogene Linked to the Aberrant Activation of Cyclic AMP/CREB Regulated GenesCancer Research, 2005
- Clear cell hidradenoma of the skin—a third tumor type with a t(11;19)‐associated TORC1–MAML2 gene fusionGenes, Chromosomes and Cancer, 2005
- Activation of cAMP Response Element-Mediated Gene Expression by Regulated Nuclear Transport of TORC ProteinsCurrent Biology, 2004
- Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumorsExperimental Cell Research, 2004
- TORCs: Transducers of Regulated CREB ActivityMolecular Cell, 2003
- Mucoepidermoid CarcinomaThe American Journal of Surgical Pathology, 2001
- Mucoepidermoid carcinoma of the major salivary glandsCancer, 1998
- UT-MUC-1, a New Mucoepidermoid Carcinoma Cell Line, and Its RadiosensitivityJAMA Otolaryngology–Head & Neck Surgery, 1992
- Mucoepidermoid carcinoma of intraoral salivary glands evaluation and application of grading criteria in 143 casesCancer, 1992
- “Low grade” mucoepidermoid carcinoma of the bronchus with “high grade” biological behaviorCancer, 1983