Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma

doi:10.1016/j.humpath.2008.11.007

Human Pathology

Volume 40, Issue 6, June 2009, Pages 854-860

https://doi.org/10.1016/j.humpath.2008.11.007 Get rights and content

Summary

The translocation t(11;19)(q21;p13) results in the gene fusion of mucoepidermoid carcinoma translocated 1–mammalian mastermind like 2 genes that is the major chromosomal abnormality observed in mucoepidermoid carcinomas of salivary glands but has not been studied in bronchopulmonary mucoepidermoid carcinoma. To investigate the importance of the mammalian mastermind like 2 gene rearrangement and mucoepidermoid carcinoma translocated 1–mammalian mastermind like 2 fusion gene in bronchopulmonary mucoepidermoid carcinoma tumorigenesis and its differential diagnosis with primary pulmonary non–small-cell carcinomas, we evaluated the presence of the mammalian mastermind like 2 gene rearrangement and the mucoepidermoid carcinoma translocated 1–mammalian mastermind like 2 fusion in formalin-fixed, paraffin-embedded tissue sections from 17 adult bronchopulmonary mucoepidermoid carcinoma, 16 adenosquamous carcinomas, 24 squamous cell carcinomas, and 41 primary adenocarcinomas by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction. We detected mammalian mastermind like 2 gene rearrangement by fluorescence in situ hybridization analysis in 13 (77%) of 17 bronchopulmonary mucoepidermoid carcinoma cases (10 of 10 being low grade and 3 of 7 being high grade). Reverse transcriptase polymerase chain reaction analysis confirmed positive fluorescence in situ hybridization results in 6 (43%) of 14 mucoepidermoid carcinoma cases. None of the squamous, adenosquamous, or adenocarcinoma cases revealed the mammalian mastermind like 2 gene rearrangement by fluorescence in situ hybridization, and the mucoepidermoid carcinoma translocated 1–mammalian mastermind like 2 fusion product by reverse transcriptase polymerase chain reaction was not identified specifically in our adenosquamous carcinoma cases. In conclusion, our study demonstrates that mammalian mastermind like 2 gene rearrangement and mucoepidermoid carcinoma translocated 1–mammalian mastermind like 2 fusion product can be detected by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction analysis performed on low- and high-grade primary bronchopulmonary mucoepidermoid carcinoma and can be used to help discriminate low- and high-grade mucoepidermoid carcinoma from adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma mimics in histologically challenging cases.

Introduction

Mucoepidermoid carcinoma (MEC) of the salivary gland is one of the most common endobronchial malignancies that occurs in the tracheobronchial tree [1]. The tumors usually contain a variable combination of mucus-secreting, squamous, and intermediate cells. Based on morphologic and cytologic features, tumors are divided into low- and high-grade subtypes. Low-grade tumors of lung have an indolent clinical course for which radical surgery is typically curative, whereas high-grade tumors have worse clinical outcome after surgery and may require adjuvant therapy [2], [3], [4]. There appears to be no association with cigarette smoking or other risk factors [1]. They have a relatively equal sex distribution and an age range of 3 to 78 years with 50% of the tumors occurring in individuals younger than 30 years [1], [4]. The pediatric population comprises a significant percentage of patients with this lesion, suggesting an underlying genetic abnormality. The t(11; 19)(q21;p13) is the major chromosomal abnormality observed in salivary gland MECs, involving 2 genes: mucoepidermoid carcinoma translocated 1 (MECT1) gene and a mammalian mastermind-like 2 (MAML2) gene located at chromosomes 19p13 and 11q21, respectively. MECT1-MAML2 fuses exon 1 of MECT1 with exons 2 to 5 of MAML2. Earlier studies indicated that MECT1-MAML2 can activate Notch target genes independent of ligand stimulation [5], [6] and that the MECT1-MAML2 fusion oncoprotein is able to activate transcription of multiple cyclic adenosine monophosphate (cAMP)/cAMP responsive element binding protein (CREB) target genes independently of exogenous signals [7], [8], inducing independent cell proliferation that results in MEC. Given the MECT1-MAML2 specific association with salivary gland MEC, we investigated its presence in a series of adult bronchopulmonary MEC, squamous cell, adenosquamous, and adenocarcinomas. Our objective was to substantiate the importance of MAML2 gene disruption and MECT1-MAML2 fusion in bronchopulmonary MEC tumorigenesis; to investigate the possibility of a common molecular pathway with squamous cell, adenosquamous, and adenocarcinomas; and to study the potential diagnostic utility of MAML2 and the MECT1-MAML2 oncogene analysis performed in formalin-fixed, paraffin-embedded tumor tissue sections. To our knowledge, no comparative MAML2 gene rearrangement analyses by fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) in paraffin sections from adult primary bronchopulmonary MEC have been published.

Section snippets

Tissue samples

The cases were selected from files of University of Pittsburgh Medical Center, Division of Anatomic Pathology and the Department of Histopathology, Royal Brompton Hospital, London UK, based on the availability of formalin-fixed, paraffin-embedded blocks from 1997 to 2008. Seventeen primary bronchopulmonary MECs, 16 primary lung adenosquamous carcinomas, 24 primary lung squamous cell carcinomas, and 41 primary lung adenocarcinoma were examined. For the adenocarcinoma cases, high-density tissue

Results

The clinical, histopathologic, and molecular profile data from our pulmonary MEC cases are summarized in Table 1, Table 2. Age of the 17 case patients MEC ranged from 23 to 82 years (mean, 45 years), with a male-female ratio of 1:2.4. Of the 17 MEC cases, 11 (65%) were parenchymal nodules without an exophytic or bronchogenic component and 6 (35%) were endobronchial tumors.

We detected the MAML2 gene rearrangement by FISH analysis in 13 (77%) of 17 MEC cases. (Fig. 3) Histologically, the 13 MEC

Discussion

MECT1 gene (also known as transducer of regulated cyclic adenosine monophosphate response element binding 1 [TORC1], Warthin and mucoepidermoid tumor translocation partner gene 1 [WAMTP1], or CREB regulated transcriptional coactivator 1 [CRTC1]) is located at chromosome 19p13. The MECT1 gene product is a binding protein for CREB. The MAML2 gene at 11q21 is the most common fusion partner for MECT1 and encodes a coactivator of Notch receptors. MAML2 gene product, after ligand stimulation, becomes

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Citation Excerpt :
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Original contributionMammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma

Summary

Introduction

Section snippets

Tissue samples

Results

Discussion

Ann Thorac Surg

Exp Cell Res

Mol Cell

J Mol Diagn

Mucoepidermoid bronchial tumors: a review of 34 operated cases

Eur J Cardiothorac Surg

Mucoepidermoid tumors of the lung

Cancer

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

Nat Genet

Mect1-Maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes

Cancer Res

Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation

EMBO J

Original contribution
Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma