CRTC1/MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin's tumors: Implications for histogenesis and biologic behavior

Abstract

We analyzed 55 primary salivary gland tumors including 22 mucoepidermoid carcinomas (MECs) to determine the association of MECT1/TORC1/CRTC1-MAML2 fusion transcript to tumor types, level of MEC differentiation and clinicopathologic parameters. Our primary salivary gland tumors were composed of 22 MECs, 11 Warthin's tumors, 10 adenoid cystic carcinomas, two basaloid carcinomas, five salivary duct carcinomas, and five adenocarcinomas, not otherwise specified. We also included, for the first time, three primary MECs of the thyroid gland. We used nested RT-PCR and subsequent sequencing techniques for detection and verification of the fusion transcript in fresh and archival specimens. Eighteen (81%) of the 22 primary salivary and one of the three thyroid glands with MEC were positive for the fusion transcript. The transcript was detected equally in low, intermediate and high grade as well as low and high stage MECs. Significant correlation between fusion negative tumors and distant metastasis was noted (P = 0.005). Four (36%) of the 11 Warthin's tumors were also positive for the transcript. None of the 22 primary non-MEC gland salivary carcinomas were positive for the transcript. We conclude that the CRTC1/MAML2 transcript may be detected in both low and high grade MEC, that fusion negative tumors may define a subset of biologically aggressive MEC's tumors, that the fusion is present in primary MECs of the thyroid gland and is also detectable in Warthin's tumor, and that a subset of MECs can be targeted for therapeutic intervention.

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

“…Moreover, all low-grade tumors were positive for the CRTC1-MAML2 gene fusion, whereas only three of the 13 high-grade mucoepidermoid carcinomas were fusion-positive. 7,12,[19][20][21] The remaining 10 fusion-negative, high-grade tumors were also negative for the EWSR1-POU5F1 fusion previously identified in high-grade mucoepidermoid carcinomas. 22 These findings support the notion that low-grade mucoepidermoid carcinomas are fusion-positive and genetically stable tumors with few genomic imbalances.…”

“…17,18 Several studies have now confirmed the initial report by Behboudi et al 19 demonstrating that the CRTC1-MAML2 fusion primarily occurs in low-grade mucoepidermoid carcinomas with a favorable clinical outcome. 12,13,20,21 A second gene fusion involving the sarcoma-associated EWSR1 gene and the stem cell regulator POU5F1 was recently identified in mucoepidermoid carcinomas with a more immature morphology compared with MAML2 positive tumors. 22 Except for the CRTC1-MAML2 fusion, little is known about other genomic rearrangements of importance for the genesis and progression of mucoepidermoid carcinoma.…”

Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer

“…The Crtc1-Maml2 fusion transcript was subsequently identified in primary thyroid, breast, cervix, lung and cutaneous sweat gland tumors with clear-cell, mucoepidermoid tumor-like histological features (Enlund et al, 2004;Behboudi et al, 2005;Kazakov et al, 2007;Tirado et al, 2007;Achcar et al, 2009;Camelo-Piragua et al, 2009;Kaye, 2009;Lennerz et al, 2009) unifying a group of tumors that arise from mucous/serous glands scattered throughout the body. As Crtc gene members are potent cAMP/CREB co-activators (Conkright et al, 2003;Iourgenko et al, 2003) and the ectopic expression of Crtc1-Maml2 activated a similar group of target genes (Coxon et al, 2005;Wu et al, 2005), a current model proposes that the fusion oncogene transforms cells by aberrantly co-activating specific Crtc1-inducible targets (Kaye, 2006).…”

Molecular Heterogeneity in Mucoepidermoid Carcinoma: Conceptual and Practical Implications

“…Interestingly, the protein can be detected in tumors suggesting reactivation of dormant developmental gene. Although the incidence of this fusion in MEC varies, it is generally accepted that more than 50 % of this entity manifest the MECT1-MAML2 [13,16,17]. Fusion-positive cases showed significantly better survival than fusion-negative cases, suggesting that MECT1-MAML2 represents a specific prognostic molecular marker in MEC.…”