Dataset Information

Mucoepidermoid Carcinoma: A Comparison of Histologic Grading Systems and Relationship to MAML2 Rearrangement and Prognosis.

ABSTRACT: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy, but categorization is complicated by variability in grading systems and uncertain prognostic significance of MAML2 rearrangement. The aims of this study were to determine the prognostic significance of MEC grading systems and MAML2 rearrangement status. Fifty-three carcinomas originally diagnosed as MEC (45 primary; 8 recurrent) of major and minor salivary glands were graded according to modified Healey, Brandwein, AFIP, and Katabi systems. Fluorescence in situ hybridization for MAML2 rearrangement was performed. Clinical features and outcomes were recorded. Twenty-five (47%) carcinomas scored the same in all grading systems. The most common histologic feature leading to a diagnosis of intermediate grade was isolated solid growth. Brandwein assigned the highest percentage of high grade (29%) and AFIP the highest percentage of low grade (80%). MAML2 was rearranged in 37/46 (80%) cases. Forty-three (81%) were morphologically compatible with MEC, and these were more likely to be low-intermediate grade and MAML2-rearranged. Of primary carcinomas, 6 (13%) recurred. Statistically significant univariate risk factors for recurrence included non-MEC morphology, stage T4, and high Brandwein grade. Margin status, MAML2 rearrangement, and isolated solid growth were not predictive of recurrence. A binary grading system (Brandwein high vs. low-plus-intermediate) could be considered to better reflect biological behavior in MEC. Our study confirms that MAML2 wildtype tumors more likely represent high grade non-MECs, and prior studies demonstrating worse prognosis in MAML2-nonrearranged MECs may be diluted by high-grade non-MECs.

SUBMITTER: Cipriani NA

PROVIDER: S-EPMC6629427 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Mucoepidermoid Carcinoma: A Comparison of Histologic Grading Systems and Relationship to MAML2 Rearrangement and Prognosis.

Cipriani Nicole A NA Lusardi Jonathan J JJ McElherne James J Pearson Alexander T AT Olivas Andrea D AD Fitzpatrick Carrie C Lingen Mark W MW Blair Elizabeth A EA

The American journal of surgical pathology 20190701 7

Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy, but categorization is complicated by variability in grading systems and uncertain prognostic significance of MAML2 rearrangement. The aims of this study were to determine the prognostic significance of MEC grading systems and MAML2 rearrangement status. Fifty-three carcinomas originally diagnosed as MEC (45 primary; 8 recurrent) of major and minor salivary glands were graded according to modified Healey, Brandwein, AFIP ...[more]

PMID: 31021855

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Project description:Mucoepidermoid carcinoma (MEC) arises in many glandular tissues and contributes to the most common malignant salivary gland cancers. MEC is specifically associated with a unique t(11;19) translocation and the resulting CRTC1-MAML2 fusion is a major oncogenic driver for MEC initiation and maintenance. However, the molecular basis underlying the CRTC1-MAML2 oncogenic functions remains elusive. Through gene expression profiling analysis, we observed that LINC00473, a long non-coding RNA (lncRNA), was the top down-regulated target in CRTC1-MAML2-depleted human MEC cells. LncRNAs belong to a new class of non-coding RNAs with emerging roles in tumorigenesis and progression, but remain poorly characterized. In this study, we investigated the role of LINC00473 in mediating CRTC1-MAML2 oncogenic activity in human MEC. We found that LINC00473 transcription was significantly induced in human CRTC1-MAML2-positive MEC cell lines and primary MEC tumors, and was tightly correlated with the CRTC1-MAML2 RNA level. LINC00473 induction was dependent on the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Depletion of LINC00473 significantly reduced the proliferation and survival of human MEC cells in vitro and blocked the in vivo tumor growth in a human MEC xenograft model. RNA in situ hybridization analysis demonstrated a predominantly nuclear localization pattern for LINC00473 in human MEC cells. Furthermore, gene expression profiling revealed that LINC00473 depletion resulted in differential expression of genes important in cancer cell growth and survival. LINC00473 likely regulates gene expression in part through its ability to bind to a cAMP signaling pathway component NONO, enhancing the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Our overall results demonstrate that LINC00473 is a downstream target and an important mediator of the CRTC1-MAML2 oncoprotein. Therefore, LINC00473 acts as a promising biomarker and therapeutic target for human CRTC1-MAML2-positive MECs.

Project description:BackgroundMucoepidermoid carcinoma (MEC) arises from multiple organs and accounts for the most common types of salivary gland malignancies. Currently, patients with unresectable and metastatic MEC have poor long-term clinical outcomes and no targeted therapies are available. The majority of MEC tumors contain a t(11;19) chromosomal translocation that fuses two genes, CRTC1 and MAML2, to generate the chimeric protein CRTC1-MAML2. CRTC1-MAML2 displays transforming activity in vitro and is required for human MEC cell growth and survival, partially due to its ability to constitutively activate CREB-mediated transcription. Consequently, CRTC1-MAML2 is implicated as a major etiologic molecular event and a therapeutic target for MEC. However, the molecular mechanisms underlying CRTC1-MAML2 oncogenic action in MEC have not yet been systematically analyzed. Elucidation of the CRTC1-MAML2-regulated transcriptional program and its underlying mechanisms will provide important insights into MEC pathogenesis that are essential for the development of targeted therapeutics.MethodsTranscriptional profiling was performed on human MEC cells with the depletion of endogenous CRTC1-MAML2 fusion or its interacting partner CREB via shRNA-mediated gene knockdown. A subset of target genes was validated via real-time RT-PCR assays. CRTC1-MAML2-perturbed molecular pathways in MEC were identified through pathway analyses. Finally, comparative analysis of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles was carried out to assess the contribution of CREB in mediating CRTC1-MAML2-induced transcription.ResultsA total of 808 differentially expressed genes were identified in human MEC cells after CRTC1-MAML2 knockdown and a subset of known and novel fusion target genes was confirmed by real-time RT-PCR. Pathway Analysis revealed that CRTC1-MAML2-regulated genes were associated with network functions that are important for cell growth, proliferation, survival, migration, and metabolism. Comparison of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles revealed common and distinct genes regulated by CRTC1-MAML2 and CREB, respectively.ConclusionThis study identified a specific CRTC1-MAML2-induced transcriptional program in human MEC cells and demonstrated that CRTC1-MAML2 regulates gene expression in CREB-dependent and independent manners. Our data provide the molecular basis underlying CRTC1-MAML2 oncogenic functions and lay a foundation for further functional investigation of CRTC1-MAML2-induced signaling in MEC initiation and maintenance.

Dataset Information

Mucoepidermoid Carcinoma: A Comparison of Histologic Grading Systems and Relationship to MAML2 Rearrangement and Prognosis.

Publications

Mucoepidermoid Carcinoma: A Comparison of Histologic Grading Systems and Relationship to MAML2 Rearrangement and Prognosis.

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