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. 2004 Aug;6(3):205–210. doi: 10.1016/S1525-1578(10)60511-9

A Study of MECT1-MAML2 in Mucoepidermoid Carcinoma and Warthin’s Tumor of Salivary Glands

Carmo Martins *†, Branca Cavaco †, Giovanni Tonon ‡, Frederic J Kaye ‡, Jorge Soares *, Isabel Fonseca *
PMCID: PMC1867632  PMID: 15269296

Abstract

The t(11;19)(q21;p13) chromosomal translocation has been described in two distinct types of salivary gland neoplasms: mucoepidermoid carcinoma (MEC) and Warthin’s tumor (WT). Since this translocation has been recently shown to generate a MECT1-MAML2 fusion gene, we evaluated 10 primary MEC and seven primary WT to further define the molecular association of these two entities using cytogenetic, as well as in situ hybridization (ISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses directed against the fusion gene. A karyotype was established in all neoplasms except for two MEC cases. Of the eight karyotyped MECs, five showed the t(11;19)(q21;p13), two had a normal karyotype, and one case presented a −Y and +X. Three of the WT revealed a normal karyotype and four had several abnormalities which did not involve chromosomes 11 and 19. ISH analysis performed in cytogenetic suspension and/or in tumor paraffin sections demonstrated MAML2 rearrangement in 7 of 10 cases of MEC: all five cases with t(11;19), one case with normal karyotype, and one unkaryotyped case. RT-PCR analysis confirmed the expression of the MECT1-MAML2 gene in all MEC cases that were positive by ISH analysis. Neither the t(11;19) nor MECT1-MAML2 was detected in any case of WT, nor in control samples from polymorphous low-grade adenocarcinoma, acinic cell carcinoma, or normal parotid gland tissue. We have demonstrated that ISH and RT-PCR are sensitive methods for detecting MECT1-MAML2 in MEC. In contrast, we did not detect the t(11;19) nor MECT1-MAML2 expression in seven cases of WT.

Mucoepidermoid carcinoma (MEC) of the salivary glands represents 5% of all salivary gland tumors and 20% of the malignant forms.1 To date, the karyotypic profile in this tumor type has only been described in 26 cases:2 in seven cases there were rearrangements of 11q14–21 and 19p12–13, mainly as a chromosomal translocation t(11;19)(q21;p12–13)3,4,5,6,7 and it was the sole abnormality in two cases.4,7 The remaining five cases showed either a more complex translocation involving other chromosomes or other rearrangements.3,5,6 The same abnormality has also been described in mucoepidermoid carcinomas originated in bronchial glands of the lung.8,9 Interestingly, the t(11;19)(q13–21;p12–13) was also reported in Warthin’s tumor (WT),10,11 a benign salivary gland neoplasm, which suggested an unexpected cytogenetic association between two otherwise unrelated salivary gland tumors. However, it is known that WT can arise and/or co-exist with MEC,12,13,14 warranting the reappraisal of this association.

The t(11;19)(q21;p13) found in MEC has recently been cloned.15 Two genes are involved: mucoepidermoid carcinoma translocated 1 (MECT1) gene and a member of the mastermind-like gene family (MAML2) located at 19p13 and 11q21, respectively.15 This translocation generates a chimeric gene MECT1-MAML2 that fuses exon 1 of MECT1 with exons 2–5 of MAML2. MECT1-MAML2 fusion product disrupts the normal mechanism of the Notch signaling pathway, activating Notch-target genes independently of exogenous signals, therefore representing a novel mechanism for altered Notch function in tumorigenesis.15 In addition, the recent identification of the MECT1 gene product as a potent co-activator for genes that are regulated by cyclic AMP responsive elements suggests that MECT1-MAML2 may be disrupting both Notch and CREB signaling pathways to induce tumorigenesis.16,17

To further substantiate the importance of the MECT1-MAML2 fusion gene in MEC tumorigenesis and to investigate a common molecular pathway with WT, we studied a series of 10 primary MEC and seven primary WT salivary gland tumors using conventional cytogenetics, in situ hybridization (ISH), and reverse transcriptase-polymerase chain reaction (RT-PCR).

Materials and Methods

Case Selection

Case selection was based on the availability of karyotypic information and/or frozen tissue from the surgical specimen. All cases with the diagnosis of mucoepidermoid carcinoma and Warthin’s tumor were reclassified according to the World Health Organization’s criteria,18 and MEC cases were graded according to Batsakis and Luna’s criteria.12,19 The clinical, histopathological, and karyotypic data are shown in Table 1.

Table 1.

Clinical, Cytogenetic, ISH, and RT-PCR Data from the Tumor Collective

Case Sex/Age Diagnosis Location Karyotype Positive FISH Positive ISH Positive RT-PCR
1 F/61 MEC grade II Parotid 46–47,XX,t(4;6)(p14;q21),t(11;19)(q21;p13)[cp5] yes yes yes
2 M/58 MEC grade III Minor Complex, not established no nt no
3 F/63 MEC oncocytic Palate 46,XX[8] nm yes yes
4 F/68 MEC grade I Parotid 46,XX,t(11;19)(q21;p13)[19] yes nr yes
5 M/78 MEC grade III Parotid 45,X,−Y[3]/46–47,XXY[cp2]/46,XY[7] nt nt no
6 F/74 MEC grade II Parotid 46,XX,t(11;19)(q21;p13)[10]/46,XX[8] yes yes yes
7 F/71 MEC grade II Parotid 46,XX,t(11;19)(q21;p13)[4]/46,XX[4] yes yes yes
8 M/39 MEC grade II Parotid 46,XY[12] nt nt no
9 F/15 MEC grade II Palate nm nt yes yes
10* F/29 MEC, ex-WT Parotid 37–47,XX,der(11)del(11)(q21)t(11;16;19)(q21;p13.3;p12 ∼ 13), der(16)del(16)(p13.3)t(11;16;19)(q21;p13.3;p12–13)del(16)(q22), der(19)del(19)(p12 ∼ 13)t(11;16;19)(q21;p13.3;p12 ∼ 13)[20] yes nr yes
11† M/67 WT Parotid 40–46,XY,add(3)(p26),del(11)(p13)[2]/46,XY[8] nt nt no
12† M/41 WT Parotid 46,XY[22] nt nt no
13† M/62 WT Parotid 46,XY[15] nt nt no
14† M/54 WT Parotid 45–47,XY,t(6;15)(p21;q15)[5]/46,XY[7] nt nt no
15† M/68 WT Parotid 46,XY[31] nt nt no
16 M/61 WT Parotid 46,XY,t(14;18)(q32;q21)[2]/46,X,−Y[3]/46,XY[6] nt nt no
17 F/46 WT Parotid 46,XX,t(5;8)(p15;q22)[2]/46,XX[10] nt nt no
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nt, not tested; nm, no metaphases; nr, no results. 

*

, Previously published as WT.26 

†

, Previously published.26 

Conventional Cytogenetic Analysis

Chromosome metaphases of tumor cells were obtained from short-term primary cultures as previously described.20 Chromosomes were GTG-banded, and the karyotypes were defined according to International System of Human Cytogenetic Nomenclature (ISCN).21 A detailed description of the tumor karyotypes is reported in Table 1.

ISH Analysis

ISH analysis was performed on cell suspension (metaphase and/or interphase nuclei) left from conventional cytogenetic analysis and on 4-μm formalin-fixed, paraffin-embedded tumor tissue sections. For the cell suspension, a standard ISH protocol with fluorescence detection (FISH) was applied.22 For the tumor tissue sections, the ISH analysis followed the method of Alers et al,23 using either fluorescence (FISH) or chromogenic (CISH) detection.

Two BAC clones probes named RP11–16K5 and RP11–676L3 that, together, cover the entire chromosome region of MAML2 gene as described by Tonon et al15 were used. The BAC clones DNA was isolated following the protocol of the distributor (Children’s Hospital Oakland Research Institute, Oakland, CA, USA). The probes were labeled by random octamer priming (Bioprime DNA Labeling, Invitrogen SA, Barcelona, Spain). For FISH procedures, the BAC clones were labeled differently with biotin and digoxigenin and detected, respectively, by Cy3-avidin (Jackson Immunoresearch Lab, West Grove, PA, USA) and anti-digoxigenin-FITC (Roche Diagnostics GmbH, Mannheim, Germany). For CISH, both BAC clones were labeled with fluorescein (FITC) using horseradish peroxidase anti-fluorescein (Roche Diagnostics GmbH) and H2O2-diaminobenzidine for visualization.

In FISH preparations, the metaphases and nuclei material were counterstained with DAPI-Vectashield mounting solution (Vector, Burlingame, CA, USA). The CISH tissue sections were counter-stained with Meyer’s hematoxylin and mounted with Entellan (Merck, Whitehouse Station, NJ, USA). The FISH and CISH signals were analyzed and recorded using a Cytovision System (Applied Imaging, Newcastle-on-Tyne, UK).

In each case, at least 200 interphase nuclei from paraffin-embedded tumor sections were evaluated. When present, normal salivary gland tissue was also analyzed. The presence of three dots (CISH preparations) or of split signals from BAC probes (FISH preparations) in more than 10% of the nuclei represent rearrangement of MAML2 gene, following the criteria of Jenkins et al.24

RT-PCR Analysis

mRNA was extracted from tissue that was frozen in liquid nitrogen immediately after surgery, using the QuickPrep Micro mRNA purification Kit (Amersham Pharmacia Biotech, Piscataway, NJ, USA), according to the manufacturer’s protocol. As controls, one case of polymorphous low-grade adenocarcinoma (PLGA), one case of acinic cell carcinoma (ACC), and tissue from one normal parotid gland were used. Synthesis of cDNA was performed with approximately 0.3 μg of mRNA, at 37°C for 90 minutes, using random primers p(dN)6 (Roche Diagnostics GmbH) and reverse transcriptase (SuperScript II RNase H−, Invitrogen SA), following the manufacturer’s instructions. Amplifications by PCR were carried out using 5 μl of cDNA, forward primer (5′-atggcgacttcgaacaatccgcggaa-3′) and reverse primer (5′-aacaggccattgccaggagaatgtgtatggg-3′). The oligonucleotide primers were designed to amplify a segment from the MECT1-MAML2 cDNA, starting in exon 1 from the MECT1 gene and finishing in exon 2 from the MAML2 gene, with an expected size of 386 bp. One μl of each PCR reaction was then used as template for a second amplification using nested forward (5′-ggaaattcagcgagaagatcg-3′) and reverse (5′-tatgggatggcagagtgttagtc-3′) primers. These oligonucleotide primers amplify a segment of the MECT1-MAML2 chimeric cDNA, starting in exon 1 from the MECT1 gene and finishing in exon 2 from the MAML2 gene, with an expected size of 339 bp. First round and nested RT-PCRs were performed over 35 cycles of amplification, using the following conditions: 95°C for 45 seconds, 56°C for 45 seconds, and 72°C for 1 minute. Amplification reactions, with a total volume of 50 μl, contained final concentrations of 20 mmol/L Tris-HCl (pH 8.4), 50 mmol/L KCl, 200 μmol/L dNTPs (Invitrogen SA), 1.5 mmol/L MgCl2, 0.6 μmol/L of each primer, and 2U of TaqDNA polymerase (Invitrogen SA). Negative controls for cDNA synthesis and PCRs, in which the template was replaced by sterile water, were included in each experiment. RNA integrity and efficiency of cDNA synthesis were confirmed in each sample by RT-PCR for the housekeeping gene phosphoglycerate kinase 1 (PGK1), using previously published oligonucleotide primers.25 Amplification with these primers yielded a 247-bp PCR product. PCR products were analyzed and purified by electrophoresis in a 2% agarose gel stained with ethidium bromide. All of the results were repeated, at least twice, from different batches of mRNA extracted at different times, from the same tumor. In the cases that presented the MECT1-MAML2 rearrangement, the PCR product was sequenced (ABI Prism 310 Genetic Analyzer, using the ABI Prism Big Dye Terminator Cycle Sequencing Ready Reaction Kit version 2.0; Applied Biosystems, Foster City, USA).

Results

Cytogenetic Analysis

Cytogenetic information was obtained from all 17 cases except for case 9 due to unsuccessful cell culture and for case 2 which showed aneuploidy and abnormal metaphases, however a karyotype could not be defined due to unsatisfactory quality (Table 1). Five of the eight fully karyotyped MEC revealed a t(11;19)(q21;p13). This was the sole abnormality found in cases 4, 6, and 7 and the translocation was present together with other aberrations in cases 1 and 10. Figure 1a illustrates the usual histological features of MEC (case 6) and Figure 1b depicts the respective karyotype containing the t(11;19)(q21;p13) as the sole karyotypic aberration. Case 10 carried a more complex translocation t(11;16;19) that involved 16p13.3 in addition to 11q21 and 19q13. This case had been initially diagnosed as a WT,26 and was reclassified as a MEC ex-WT (Figure 2a, case 10). Figure 2b illustrates the karyotype of case 10. Case 5 demonstrated two small clones with either loss of Y or gain of X and the remaining two MEC cases 3 and 8 had a normal karyotype. The series of WT contained three cases (12, 13, and 15) with normal karyotype and four with several abnormalities. None involved rearrangements of chromosome 11 and 19.

Figure 1.

Figure 1

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Mucoepidermoid carcinoma case 6 with a t(11;19)(q21;p13). a: Case 6 is a typical MEC, with mucin producing cells (ii), intermediate (iii), and squamous (i) cells (H&E). b: Representative karyotype showing the t(11;19) as the sole karyotypic abnormality. c: FISH analysis on a metaphase spread with the BAC clones probes RP11–16K5 (green) and RP11–676L3 (red) for MAML2 gene showing the intragenic rearrangement of the gene: the hybridization probes are either located immediately adjacent in normal chromosome 11, or separated, one (green) from RP11–16k5 on der19 and the other (red) from RP11–676L3 on der11. d: FISH analysis on a paraffin tumor section with the BAC probes RP11–16K5 (red) and RP11–676L3 (green) for MAML2 gene showing the intragenic rearrangement of the gene in interphase nuclei: the hybridization signals from both BAC probes are either located in close proximity indicating the normal gene MAML2 or separated indicating rearrangement of the gene. e: CISH analysis of a tumor section from paraffin-embedded tissue. Both BAC clones probes RP11–16K5 and RP11–676L3 for MAML2 gene were labeled with FITC and detected with DAB-chromogen (brown). There is an intragenic rearrangement of the gene in interphase nuclei: three brown spots could be observed representing one of them the normal copy of MAML2 gene and two smaller signals the split of the gene. f: CISH analysis of normal salivary gland tissue, of the same section (e), using the same BAC probes, showing two spots per nucleus.

Figure 2.

Figure 2

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Mucoepidermoid carcinoma case 10 with a t(11;16;19)(q21;p13.3;p13). a: In low-power view the tumor presents cystic spaces, lined by eosinophylic cells and has a prominent lymphoid infiltration with follicules with germinal centers. Higher power demonstrates that the lining of the cysts is composed of the three cell populations that are diagnostic of MEC (H&E). b: Representative karyotype showing the t(11;16;19)(q21;p13.3;p13). c: FISH analysis on a metaphase spread with the BAC clones RP11–16K5 (green) and RP11–676L38 (red) for MAML2 gene showing the intragenic rearrangement of the gene: both hybridization signals are immediately adjacent in normal chromosome 11, the hybridization signal from RP11–16k5 on der16 and the hybridization signal from RP11–676L3 on der11.

ISH Analysis

FISH Analysis on Cell Suspension

The five MEC cases with t(11;19) and case 2 were probed with the BAC clones probes RP11–16K5 and RP11–676L3 using FISH (Table 1). Rearrangement of MAML2 gene in the t(11;19) positive cases was confirmed by a split signal from the two BAC clones. On metaphases, the signal from clone RP11–16K5, which contains the exon 1 of MAML2 gene15 was detected on der19 and the signal from clone RP11–676L3 on der11 (Figure 1c). In case 10, the signals from MAML2 BAC clones were found on der11 and der16 (Figure 2c). Case 2, without karyotypic evidence of 11q21 and 19p13 rearrangements, showed no split signal.

ISH Analysis on Paraffin Sections

ISH analysis was performed in paraffin tumor tissue sections to verify MAML2 rearrangements in uncultured tumor cells, in situ, and to compare the results obtained with cytogenetic and RT-PCR analysis. ISH was applied to seven MEC cases: this included all of the t(11;19) G-band positive cases, as well as case 3 with a normal karyotype and case 9 which could not be karyotyped (Table 1). Except for cases 4 and 10, where the signals could not be evaluated due to poor hybridization, all remaining cases confirmed MAML2 rearrangement shown in FISH preparations by a split signal from BAC probes (Figure 1d) and in CISH by three brown dots (Figure 1e) in more than 10% of the cells. No MAML2 rearrangement was observed in normal tissue (Figure 1f).

RT-PCR Analysis

To investigate the expression of the MECT1-MAML2 chimeric gene, we carried out RT-PCR using tumor mRNA (Table 1). This analysis revealed the expression of the rearrangement between MECT1 and MAML2 genes in seven of the 10 (70%) mucoepidermoid carcinomas, but in none of the seven WT (Figure 3). Sequencing analysis of the positive RT-PCR products confirmed the presence of the same rearrangement in the seven MECs, with the fusion product between MECT1 exon 1 and MAML2 exon 2. There was no expression of this rearrangement either in the two salivary glands carcinomas (ACC and PLGA) or in the normal salivary gland used as controls (Figure 3). We also carried out nested RT-PCR, which confirmed the results obtained in the first PCR (data not shown). The 247-bp RT-PCR product for the PGK1 housekeeping gene was detected in all 20 samples, indicating adequate sampling and confirming mRNA integrity (Figure 3).

Figure 3.

Figure 3

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First round RT-PCR analysis of MECT1-MAML2 fusion gene transcript, using MECT1 exon 1 (sense) and MAML2 exon 2 (antisense) oligonucleotide primers. RT-PCR products were resolved by electrophoresis on a 2% ethidium bromide-stained agarose gel and visualized on an UV source. MECs are numbered according to Table 1. MECT1-MAML2 transcript (386-bp) is present in 7 of the 10 MECs, but not in seven Warthin’s tumors (data shown only for Warthin’s tumor 11), one PLGA, one ACC and one normal salivary gland (NSG). Replacing template with water (indicated as BL) yielded no product for both MECT1-MAML2 and PGK1 RT-PCRs. The detection of a 247-bp PGK1 RT-PCR product confirmed mRNA integrity in all of the samples. Lane 1: DNA molecular weight marker VIII (Roche Diagnostics GmbH).

Discussion

A chromosomal translocation may be considered characteristic for a given cancer if it is detected frequently and, most importantly, if it occurs as the sole cytogenetic abnormality. The t(11;19)(q21;p12–13) chromosomal translocation meets these criteria as it is the most frequently detected aberration (27%) in MEC, either as the unique abnormality or together with other chromosome abnormalities.3,4,5,6,7,8,9 The molecular cloning of the t(11;19)(q21;p13) translocation in two cell lines generated from lung and parotid gland MEC15 has now allowed for specific RT-PCR and ISH to complement standard cytogenetics in the genetic characterization of malignant salivary gland tumors.

To evaluate the incidence of MECT1-MAML2 fusion gene, we selected a series of 10 primary MEC which were cytogenetically characterized and then analyzed by ISH and RT-PCR. Additionally, seven WT cases were included in this study because a similar translocation t(11;19)(q13–21;p12–13) has been previously described in some of these tumors.10,11 In addition, Enlund et al27 reported that one case classified as WT and displaying a t(11;19) expressed the MECT1-MAML2 fusion gene. WT and MEC are two otherwise unrelated salivary gland tumors that do not share clinicopathological features, and their accepted histogenesis is also distinct.28 However, there are a few reports on the co-existence of both histological types in the same gland lesion,13,14 which might be an explanation for the finding of a common genetic alterations. Case 10 (reported herein) is an example of such a situation. In addition, Case 1 represents an otherwise typical MEC but it also contains foci with a WT-like pattern.

All cases classified as MEC were evaluated by RT-PCR analysis to investigate the presence of expression of the fusion gene, using frozen tumor tissue. RT-PCR analysis detected MECT1-MAML2 in all cases carrying the t(11;19) together with two other cases (one with normal karyotype, and one with an unsuccessful karyotyping). The expression of the chimeric gene in the case showing a normal karyotype is not unexpected. Normal karyotypes are known to occur in neoplasms due to contamination and/or overgrowth of normal elements such as lymphocytes and fibroblasts, or due to the insufficient resolution of conventional cytogenetics to recognize submicroscopic alterations. RT-PCR detection of the chimeric gene, therefore, proved to be a more sensitive approach for the diagnosis of genetic lesions in MEC than cytogenetic analysis. With the former method, we detected MECT1-MALM2 fusion gene in 70% of the cases, as compared to 50% identified by conventional cytogenetics. In the appropriate clinical and histological setting, this leads to a potential usefulness of MECT1-MALM2 as a molecular marker to make the diagnosis of mucoepidermoid carcinoma. In contrast, we did not detect the t(11;19) nor MECT1-MALM2 expression in any of the seven primary WT samples.

RT-PCR, however, is hampered by the necessity to obtain suitable undegraded RNA from primary biopsy samples which may not be feasible in many situations. To circumvent this problem, we applied ISH analysis to paraffin-embedded tumor tissue sections to verify the presence of MAML2 gene rearrangement in positive RT-PCR cases. The ISH technique performed on paraffin sections allows for the evaluation of the genetic alterations in situ, avoiding in vitro manipulation and the need for fresh tissue. In tumor sections, the MAML2 rearrangement was successfully detected in five out of seven cases: in three t(11;19) G-band positive cases, in one normal G-band case, and in one unkaryotyped case which confirmed our RT-PCR results. In the remaining two cases, both t(11;19) G-band positive, no signal was obtained with the ISH analysis which was due to either poor fixation and/or preservation of the tissue fragments. Although the RT-PCR methodology appears to be the most sensitive technique for detecting MECT1-MAML2, the ISH approach is a reliable method that may allow the molecular diagnosis in extended case series where archival material can be used. Future studies using a larger series will ultimately define the proper role of RT-PCR and ISH for the diagnosis of MEC.

In cases 2, 5, and 8 there was no expression of the MECT1-MAML2 fusion gene. None of these cases had a detectable t(11;19). The absence of MECT1-MAML2 in 3 of 10 MEC samples warrants additional investigation and suggests an alternate genetic basis for this subset of salivary gland tumors. The cytogenetic information from published MEC case series show other recurrent chromosome aberrations, such as rearrangements affecting the chromosome region 6q21–2529,31,32 and numerical abnormalities, such as loss of chromosome Y, and gains of chromosomes 2, 3, 5, 7, 18, 20, and X.5,6,29,31,32,33,34,35,36 Some of these alterations are detected with the t(11;19) which might indicate they are secondary changes. However, some of them, such as the 6q rearrangements, are not associated with the t(11;19) chromosomal translocation. The role of these recurrent changes in the pathways of MEC carcinogenesis needs further clarification.

In conclusion, our data confirms and significantly extends the number of cases that have been analyzed to date, demonstrating a key role for the MECT1-MAML2 fusion gene on MEC biology and also supporting the usefulness of ISH and RT-PCR for diagnosis, especially in histologically challenging cases. In contrast, MECT1-MAML2 expression appears to be a rare event in WT samples that do not contain concomitant evidence for MEC.

Acknowledgments

We thank Lúcia Roque, B.Sc., Ph.D. and Valeriano Leite, M.D., Ph.D. for scientific advice and critical reading of the manuscript.

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