title: Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene.
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.
authors.affiliation: Lundberg Laboratory for Cancer Research, Department of Pathology, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
authors.forename: Afrouz
authors.initials: A
authors.lastname: Behboudi
authors.forename: Fredrik
authors.initials: F
authors.lastname: Enlund
authors.forename: Marta
authors.initials: M
authors.lastname: Winnes
authors.forename: Ywonne
authors.initials: Y
authors.lastname: Andrén
authors.forename: Anders
authors.initials: A
authors.lastname: Nordkvist
authors.forename: Ilmo
authors.initials: I
authors.lastname: Leivo
authors.forename: Emilie
authors.initials: E
authors.lastname: Flaberg
authors.forename: Laszlo
authors.initials: L
authors.lastname: Szekely
authors.forename: Antti
authors.initials: A
authors.lastname: Mäkitie
authors.forename: Reidar
authors.initials: R
authors.lastname: Grenman
authors.forename: Joachim
authors.initials: J
authors.lastname: Mark
authors.forename: Göran
authors.initials: G
authors.lastname: Stenman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D018277:Carcinoma, Mucoepidermoid / Q000145:classification* / Q000235:genetics; D002648:Child; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D009857:Oncogenes; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; C495418:MECT1-MAML2 fusion protein, human; D015514:Oncogene Proteins, Fusion