Purpose: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. To explore the genetic origins of MEC, we performed systematic genomic analyses of these tumors. Experimental Design: Whole-exome sequencing and gene copy-number analyses were performed for 18 primary cancers with matched normal tissue. FISH was used to determine the presence or absence of the MECT1-MAML2 translocation in 17 tumors. Results: TP53 was the most commonly mutated gene in MEC (28%), and mutations were found only in intermediate- and high-grade tumors. Tumors with TP53 mutations had more mutations overall than tumors without TP53 mutations (P = 0.006). POU6F2 was the second most frequently mutated gene, found in three low-grade MECs with the same in-frame deletion. Somatic alterations in IRAK1, MAP3K9, ITGAL, ERBB4, OTOGL, KMT2C, and OBSCN were identified in at least two of the 18 tumors sequenced. FISH analysis confirmed the presence of the MECT1-MAML2 translocation in 15 of 17 tumors (88%). Conclusions: Through these integrated genomic analyses, MECT1-MAML2 translocation and somatic TP53 and POU6F2 mutations appear to be the main drivers of MEC.
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