Emerging Biology of Malignant Salivary Gland Tumors Offers New Insights into the Classification and Treatment of Mucoepidermoid Cancer

Kaye, Frederic J.

doi:10.1158/1078-0432.ccr-06-0791

Cited by 28 publications

(19 citation statements)

References 30 publications

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“…Interestingly, the same CRTC1/MAML2 fusion gene was also detected in a Warthin's tumor with a t(11;19) translocation and in a clear cell hidradenoma of skin (Behboudi et al, 2005;El-Naggar, 2006). These findings raise the issue of tumor specificity and the possible histogenetic and biological effect of this event in the development of these entities (El-Naggar, 2006;Kaye, 2006). More recently, clinicopathologic studies of MECs have reported a restricted detection of the fusion transcript to the low-grade phenotype implying that this alteration imparts differentiation arrest and benign clinical behavior (Martins et al, 2004;Behboudi et al, 2006;Okabe et al, 2006).…”

Section: Introductionmentioning

confidence: 79%

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

Tirado

Williams

Hanna

et al. 2007

Genes Chromosomes & Cancer

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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.

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Section: Introductionmentioning

confidence: 79%

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

Tirado

Williams

Hanna

et al. 2007

Genes Chromosomes & Cancer

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188

182

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“…RT-PCR is considered preferable to conventional cytogenetic analysis in this regard, but is hampered by poor tissue fixation in the paraffin embedded sections [12]. The translocation is more commonly observed in RNA obtained from snap-frozen samples as compared to formalin-fixed tissue which suggests that even adequately fixed specimens may show false negativity due to technical reasons [13]. The specimen in our case was properly fixed and did not need decalcification, however the need for decalcification in most of the central MECs may also similarly impinge on the results.…”

Section: Discussionmentioning

confidence: 99%

Central Mucoepidermoid Carcinoma, A Case Report with Molecular Analysis of the TORC1/MAML2 Gene Fusion

Khan

Loya

Azhar

et al. 2010

Head and Neck Pathol

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Mucoepidermoid carcinoma is the most common salivary gland malignancy. The majorities of these tumors arise in the parotid and minor salivary glands, but may rarely develop intraosseously. The latter is not uncommonly associated with diagnostic and management difficulties. We report an example of intraosseous mucoepidermoid carcinoma with positive TORC1/MAML2 gene fusion transcript and discuss the clinical implications.

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“…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). For example, using a doxycycline inducible Crtc1-Maml2 vector system we identified marked induction of previously known cAMP target genes, such as PEPCK, amphiregulin, NR4A2 and NR4A3 (Coxon et al, 2005), which corresponded to the prototypic gene promoters activated by wild-type Crtc1 (Conkright et al, 2003;Iourgenko et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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Activation of Crtc1 (also known as Mect1/Torc1) by a t(11;19) chromosomal rearrangement underlies the etiology of malignant salivary gland tumors. As LKB1 is a target for mutational inactivation in lung cancer and was recently shown to regulate hepatic Crtc2/CREB transcriptional activity in mice, we now present evidence suggesting disruption of an LKB1/Crtc pathway in cancer. Although Crtc1 is preferentially expressed in adult brain tissues, we observed elevated levels of steadystate Crtc1 in thoracic tumors. In addition, we show that somatic loss of LKB1 is associated with underphosphorylation of endogenous Crtc1, enhanced Crtc1 nuclear localization and enhanced expression of the Crtc prototypic target gene, NR4A2/Nurr1. Inhibition of NR4A2 was associated with growth suppression of LKB1 null tumors, but showed little effect on LKB1-wildtype cells. These data strengthen the role of dysregulated Crtc as a bona fide cancer gene, present a new element to the complex LKB1 tumorigenic axis, and suggest that Crtc genes may be aberrantly activated in a wider range of common adult malignancies.

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Emerging Biology of Malignant Salivary Gland Tumors Offers New Insights into the Classification and Treatment of Mucoepidermoid Cancer

Cited by 28 publications

References 30 publications

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

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

Central Mucoepidermoid Carcinoma, A Case Report with Molecular Analysis of the TORC1/MAML2 Gene Fusion

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

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