t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway

Tonon, Giovanni; Modi, Sanjay; Wu, Lizi; Kubo, Akihito; Coxon, Amy; Komiya, Takefumi; O’Neil, Kevin M.; Stover, Kristen; El‐Naggar, Adel K.; Griffin, James D.; Kirsch, Ilan R.; Kaye, Frederic J.

doi:10.1038/ng1083

Cited by 514 publications

(463 citation statements)

References 30 publications

(43 reference statements)

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“…limited sampling, ulcerated tumors without surface component, nodal metastases) exist in which the distinction between a MEC and a relatively bland non-keratinizing AsqCA may be greatly facilitated by ancillary testing, since common translocations exist that are fairly specific for MEC and are not seen in AsqCA. The t(11;19)(q21;p13) translocation results in a CRTC1-MAML2 fusion (previously known as MECT1-MAML2) [7], and the t(11;15)(q21;q26) results in a fusion of CRTC3-MAML2 [8]. These are noted in 70 % of MEC overall, and in recent studies may be present in a considerable proportion of even high grade MEC, assuming rigorous exclusion of other entities (like AsqCA) [6].…”

Section: Discussionmentioning

confidence: 99%

“…AsqCA are more aggressive than MEC as a whole, and likely more aggressive even when comparing to high grade MEC alone [1,2,6]. Additionally, at least two reproducible translocations: CRTC1-MAML2 (previously known as MECT1-MAML2) [6,7], and CRTC3-MAML2 [8] characterize the majority of MEC, whereas no reproducible genetic alterations exist for AsqCA. More recently, Alos et al [9] have outlined specific criteria that are currently the standard to delineate & Raja R. Seethala seethalarr@upmc.edu…”

Section: Introductionmentioning

confidence: 99%

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Ciliated Adenosquamous Carcinoma: Expanding the Phenotypic Diversity of Human Papillomavirus-Associated Tumors

Radkay-Gonzalez

Faquin

McHugh

et al. 2015

Head and Neck Pathol

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This study describes a unique subset of ciliated, human papillomavirus (HPV) related, adenosquamous carcinomas (AsqCA) of the head and neck that in contrast to most AsqCA, often show areas with lower grade cytonuclear features. They are comprised of largely nonkeratinizing squamous cell carcinoma components with cystic change, gland formation, mucin production, and cilia in tumor cells. Seven cases of ciliated AsqCA were retrieved. Site distribution was as follows: palatine tonsil-3/7, base of tongue-1/7, and neck (unknown primary site)-3/7. Despite the occasional resemblance to mucoepidermoid carcinoma (MEC), the tumors showed focal keratinizing morphology and atypia, and all tumors were negative for MAML2 rearrangements. Oropharyngeal and neck tumors were uniformly p16 positive and showed punctate staining by in situ hybridization for high risk HPV DNA. There were two distant metastases (lung), and one tumor related death. Thus, ciliated AsqCA are HPV-associated lesions that pose unique pitfalls, closely mimicking MEC and other salivary gland tumors. These tumors add to the list of those which defy the dogma that ciliated epithelium always equates to a benign process.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ciliated Adenosquamous Carcinoma: Expanding the Phenotypic Diversity of Human Papillomavirus-Associated Tumors

Radkay-Gonzalez

Faquin

McHugh

et al. 2015

Head and Neck Pathol

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“…We have now identified another element to this pathway by observing that somatic loss of LKB1 in tumor cell lines is associated with enhanced Crtc1 activation resulting in deregulated expression of several cAMP/ CREB-inducible targets, including NR4A2/Nurr1. We and others had previously shown that Crtc1 is a bona fide cancer gene when activated by a t(11;19) chromosomal translocation resulting in the aberrant transcription of certain Crtc1 inducible genes, including the orphan nuclear receptor NR4A2 (Tonon et al, 2003;Coxon et al, 2005;Wu et al, 2005). As LKB1 has been identified as a key regulator for Crtc2 transcriptional activity (Shaw et al, 2005;Katoh et al, 2006) and because somatic mutations have been identified in a subset of human lung tumors and cell lines (Sanchez-Cespedes et al, 2002;Ji et al, 2007), our data now suggest that enhanced Crtc gene family activity may participate in the tumorigenic process within LKB1 null tumors that are not otherwise associated with the recurrent t(11;19) rearrangement.…”

Section: Discussionmentioning

confidence: 99%

“…The Crtc1 (aka Mect1/Torc1) gene was initially isolated as a fusion partner with Maml2 in mucoepidermoid salivary gland and lung tumors that carry a t(11;19) chromosomal rearrangement (Tonon et al, 2003). 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.…”

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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“…13,14 Subsequent studies revealed that it results in a CRTC1-MAML2 fusion in which the N-terminal Notch-binding domain of the coactivator MAML2 (Mastermind-like 2) is replaced by the CREBbinding domain of CRTC1. 15,16 An important molecular consequence of the fusion is the activation of cAMP/CREB target genes (Enlund et al, unpublished data). 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.…”

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confidence: 99%

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

et al. 2013

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Mucoepidermoid carcinoma is the most common salivary gland malignancy, and includes a spectrum of lesions ranging from non-aggressive low-grade tumors to aggressive high-grade tumors. To further characterize this heterogeneous group of tumors we have performed a comprehensive analysis of copy number alterations and CRTC1-MAML2 fusion status in a series of 28 mucoepidermoid carcinomas. The CRTC1-MAML2 fusion was detected by RT-PCR or fluorescence in situ hybridization in 18 of 28 mucoepidermoid carcinomas (64%). All 15 low-grade tumors were fusion-positive whereas only 3 of 13 high-grade tumors were fusion-positive. Highresolution array-based comparative genomic hybridization revealed that fusion-positive tumors had significantly fewer copy number alterations/tumor compared with fusion-negative tumors (1.5 vs 9.5; P ¼ 0.002). Twelve of 18 fusion-positive tumors had normal genomic profiles whereas only 1 out of 10 fusionnegative tumors lacked copy number alterations. The profiles of fusion-positive and fusion-negative tumors were very similar to those of low-and high-grade tumors. Thus, low-grade mucoepidermoid carcinomas had significantly fewer copy number alterations/tumor compared with high-grade mucoepidermoid carcinomas (0.7 vs 8.6; Po0.0001). The most frequent copy number alterations detected were losses of 18q12.2-qter (including the tumor suppressor genes DCC, SMAD4, and GALR1), 9p21.3 (including the tumor suppressor genes CDKN2A/B), 6q22.1-q23.1, and 8pter-p12.1, and gains of 8q24.3 (including the oncogene MAFA), 11q12.3-q13.2, 3q26.1-q28, 19p13.2-p13.11, and 8q11.1-q12.2 (including the oncogenes LYN, MOS, and PLAG1). On the basis of these results we propose that mucoepidermoid carcinoma may be subdivided in (i) low-grade, fusion-positive mucoepidermoid carcinomas with no or few genomic imbalances and favorable prognosis, (ii) high-grade, fusion-positive mucoepidermoid carcinomas with multiple genomic imbalances and unfavorable prognosis, and (iii) a heterogeneous group of high-grade, fusion-negative adenocarcinomas with multiple genomic imbalances and unfavorable outcome. Taken together, our studies indicate that molecular genetic analysis can be a useful adjunct to histologic scoring of mucoepidermoid carcinoma and may lead to development of new clinical guidelines for management of these patients.

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t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway

Cited by 514 publications

References 30 publications

Ciliated Adenosquamous Carcinoma: Expanding the Phenotypic Diversity of Human Papillomavirus-Associated Tumors

Ciliated Adenosquamous Carcinoma: Expanding the Phenotypic Diversity of Human Papillomavirus-Associated Tumors

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

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

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