Carcinoma ex pleomorphic adenoma (Ca‐ex‐PA) is an epithelial malignancy developing within a benign salivary gland pleomorphic adenoma (PA). Here we have used genome‐wide, high‐resolution array‐CGH, and fluorescence in situ hybridization to identify genes amplified in double min chromosomes and homogeneously staining regions in PA and Ca‐ex‐PA and to identify additional genomic imbalances characteristic of these tumor types. Ten of the 16 tumors analyzed showed amplification/gain of a 30‐kb minimal common region, consisting of the 5′‐part of HMGA2 (encoding the three DNA‐binding domains). Coamplification of MDM2 was found in nine tumors. Five tumors had cryptic HMGA2‐WIF1 gene fusions with amplification of the fusion oncogene in four tumors. Expression analysis of eight amplified candidate genes in 12q revealed that tumors with amplification/rearrangement of HMGA2 and MDM2 had significantly higher expression levels when compared with tumors without amplification. Analysis of individual HMGA2 exons showed that the expression of exons 3–5 were substantially reduced when compared with exons 1–2 in 9 of 10 tumors with HMGA2 activation, indicating that gene fusions and rearrangements of HMGA2 are common in tumors with amplification. In addition, recurrent amplifications/gains of 1q11‐q32.1, 2p16.1‐p12, 8q12.1, 8q22‐24.1, and 20, and losses of 1p21.3‐p21.1, 5q23.2‐q31.2, 8p, 10q21.3, and 15q11.2 were identified. Collectively, our results identify HMGA2 and MDM2 as amplification targets in PA and Ca‐ex‐PA and suggest that amplification of 12q genes (in particular MDM2 ), deletions of 5q23.2‐q31.2, gains of 8q12.1 ( PLAG1 ) and 8q22.1‐q24.1 ( MYC ), and amplification of ERBB2 may be of importance for malignant transformation of benign PA. © 2008 Wiley‐Liss, Inc.

Recently, gene fusions between the androgen responsive gene TMPRSS2 and members of the ETS-family of DNA-binding transcription factor genes were found in prostate cancer. Recurrent fusions were identified between the 5'-noncoding region of TMPRSS2 and ERG, or less frequently ETV1 or ETV4, resulting in overexpression of normal or truncated ETS-proteins. Herein, we have analyzed a series of 50 prostate cancer samples for expression of TPRSS2-ERG and TMPRSS2-ETV1 fusion transcripts. RT-PCR analysis revealed TMPRSS2-ERG fusion transcripts in 18 of the 50 tumors (36%). None of the tumors expressed a TMPRSS2-ETV1 fusion. Our findings show that the TMPRSS2-ERG fusion is common in prostate cancer and that the related TMPRSS2-ETV1 fusion is very rare. However, the frequency of ERG-fusions in the present study is somewhat lower than previously observed, indicating heterogeneity with regard to expression of ETS-gene fusions in subsets of prostate cancers. Moreover, clinical follow-up studies showed a clear tendency that fusion-positive tumors were associated with lower Gleason grade and better survival than fusion-negative tumors. Our findings suggest that ERG gene fusions might be of prognostic significance in prostate cancer.

Fusion of the CREB regulated transcription coactivator CRTC1 (a.k.a. MECT1, TORC1, or WAMTP1) to the Notch coactivator MAML2 is a characteristic feature of low‐grade mucoepidermoid carcinomas of salivary and bronchial glands. The CRTC1–MAML2 fusion protein acts by inducing transcription of cAMP/CREB target genes, and this activity is crucial for the transforming properties of the protein. Here we show that the CRTC1–MAML2 gene fusion is also frequent in benign hidradenomas of the skin. FISH and RT‐PCR analyses revealed that hidradenomas are genetically heterogeneous, and that 10 of the 20 tumors analyzed (50%) contained the CRTC1–MAML2 gene fusion and expressed the resulting fusion transcript. Immunohistochemical analysis demonstrated expression of the fusion protein in the majority of tumor cells, including clear cells, poroid cells, and cells with epidermoid and ductal differentiation. In addition, we could show that all fusion‐positive tumors were morphologically distinguished by the presence of more or less abundant areas of clear cells whereas all fusion‐negative tumors lacked clear cells. Our findings thus demonstrate that the CRTC1–MAML2 gene fusion is frequent in hidradenomas and is associated with clear cell variants of this tumor. Taken together, the present and previous observations indicate that the CRTC1–MAML2 fusion is etiologically linked to benign and low‐grade malignant tumors originating from diverse exocrine glands rather than being linked to a separate tumor entity. © 2007 Wiley‐Liss, Inc.

We have recently shown in the BDII rat model of human endometrial adenocarcinoma (EAC), rat chromosome 10 (RNO10) is frequently involved in chromosomal aberrations. In the present study, we investigated the association between RNO10 deletions, allelic imbalance (AI) at RNO10q24 and Tp53 mutation in 27 rat EAC tumors. We detected chromosomal breakage accompanied by loss of proximal and/or gain of distal parts of RNO10 in approximately 2/3 of the tumors. This finding is suggestive of a tumor suppressor activity encoded from the proximal RNO10. Given the fact that Tp53 is located at RNO10q24-q25, we then performed Tp53 mutation analysis. However, we could not find a strong correlation between AI/deletions at RNO10q24 and Tp53 mutation. Instead, the observed patterns for AI, chromosomal breaks and deletions suggest that major selection was directed against a region located close to, but distal of Tp53. In different human malignancies a similar situation of AI at chromosome band 17p13.3 (HSA17p13.3) unassociated with TP53 mutation has been observed. Although RNO10 is largely homologous to HSA17, the conservation with respect to gene order among them is not extensive. We utilized publicly available draft DNA sequences to study intrachromosomal rearrangement during the divergence between HSA17 and RNO10. By using reciprocal comparison of rat and human genome data, we could substantially narrow down the candidate tumor suppressor region in rat from 3 Mb to a chromosomal segment of about 0.5 Mb in size. These results provide scientific groundwork for identification of the putative tumor suppressor gene(s) at 17p13.3 in human tumors.

We have previously identified a subgroup of pleomorphic salivary gland adenomas with ring chromosomes of uncertain derivation. Here, we have used spectral karyotyping (SKY), fluorescence in situ hybridization (FISH) and high-resolution oligonucleotide array-CGH to determine the origin and content of these rings and to identify genes disrupted as a result of ring formation. Of 16 tumors with rings, 11 were derived from chromosome 8, 3 from chromosome 5 and 1 each from chromosomes 1, 6 and 9. Array-CGH revealed that 10/11 r(8) consisted of amplification of a 19 Mb pericentromeric segment with recurrent breakpoints in FGFR1 in 8p12 and in PLAG1 in 8q12.1. Molecular analyses revealed that ring formation consistently generated novel FGFR1–PLAG1 gene fusions in which the 5′-part of FGFR1 is linked to the coding sequence of PLAG1. An alternative mechanism of PLAG1 activation was found in tumors with copy number gain of an intact PLAG1 gene. Rings derived from chromosomes 1, 5, 6 or 9 did not result in gene fusions, but rather resulted in losses indicative of the involvement of putative tumor suppressor genes on 8p, 5p, 5q and/or 6q. Our findings also reveal a novel mechanism by which FGFR1 contributes to oncogenesis and further illustrate the versatility of the FGFR1 and PLAG1 genes in tumorigenesis.

Recent studies have shown that mucoepidermoid carcinomas (MECs) of the salivary and bronchial glands are characterized by a recurrent t(11;19)(q21;p13) translocation, resulting in a MECT1-MAML2 fusion in which the cAMP response element binding protein (CREB)-binding domain of the CREB-regulated transcriptional coactivator MECT1 (also known as CRTC1, WAMTP1, or TORC1) is fused to the transactivation domain of the Notch coactivator MAML2. The molecular consequences of the fusion are still largely uncertain. Earlier studies have indicated that MECT1MAML2 can activate Notch signaling independent of ligand stimulation, and recent studies have demonstrated that MECT1-MAML2 can activate transcription of multiple cAMP/CREB target genes in vitro and that the N-terminal CREB-binding domain is crucial for the transforming activity of the fusion protein. Collectively, these studies indicate that MECT1-MAML2 is a multifunctional protein with effects on several signaling pathways. Interestingly, recent studies have indicated that the MECT1-MAML2 fusion may not exclusively occur in MEC but may also be found in other types of glandular tumors. Thus, we have identified the fusion in two apparently unrelated benign tumor types: Warthin’s tumor (WAT) and clear cell hidradenoma of the skin. In this respect, MECT1-MAML2 is reminiscent of the ETV6-NTRK3 fusion that has been encountered in tumors originating from multiple cell lineages. We read with interest the study by Martins et al in The Journal of Molecular Diagnostics in which they studied the MECT1-MAML2 fusion in 10 MECs and 7 WATs using fluorescence in situ hybridization (FISH) and/or reverse transcriptase-polymerase chain reaction. The fusion was detected in seven MECs but in none of the WATs. It should be noted that none of the classical WATs in this study had a t(11;19) translocation. However, one of their translocationand fusion-positive MECs (case 10) was of particular interest because it was originally diagnosed and published as a benign WAT. This tumor was now reclassified as a MEC ex WAT. As indicated by the authors, it is known that MECs in rare instances may arise from or coexist with WAT. Case 10 in their series was suggested to represent such a case. The authors conclude that the MECT1-MAML2 fusion appears to be rare in WATs that do not contain concomitant evidence of MEC and that the fusion might be a useful diagnostic marker for MEC, especially in histologically challenging cases. The observations by Martins et al prompted us to reexamine our previously published t(11;19)and fusionpositive WAT both histologically and molecularly. Analysis of tissue sections from multiple levels of this tumor confirmed the original diagnosis of a benign WAT. Despite extensive sampling, we found no areas reminiscent of MEC in any of the sections examined. To further characterize this tumor, we also performed FISH on paraffin sections using a dual-color break-apart rearrangement probe for MAML2. Rearrangements of MAML2, indicating a MECT1-MAML2 fusion, were only detected in the morphologically benign tumor cells lining the duct-like structures and cysts of the tumor (Figure 1A). Split signals were not observed in the surrounding lymphoid cells, supporting the concept that these cells are non-neoplastic stromal cells. Immunostaining of the tumor using a MECT1-MAML2 polyclonal antibody revealed nuclear staining of the benign tumor cells lining the duct-like structures and cysts, in agreement with the FISH results (Figure 1B). The surrounding lymphoid cells were mainly negative. Taken together, our results show that the present tumor represents a benign WAT with a MECT1-MAML2 gene fusion. Available data do, however, indicate that the fusion presumably is rare in WAT. In addition to the present case, there is only one previously reported WAT with a t(11;19)(q21;p13) translocation and one case with a possible variant translocation t(11;16)(q13–14;q23). The fact that the MECT1-MAML2 fusion may also infrequently occur in WAT is important to consider when using the fusion as a diagnostic marker for MEC. This is particularly important in metaplastic variants of WAT with atypia and mitotic activity, which may simulate MEC. Our findings of the MECT1-MAML2 fusion in two unrelated benign tumor types are of particular interest in relation to recent data showing that MECT1-MAML2 preferentially occurs in low-grade MECs and that fusionJournal of Molecular Diagnostics, Vol. 8, No. 3, July 2006

Mucoepidermoid carcinomas (MECs) of the salivary and bronchial glands are characterized by a recurrent t(11;19)(q21;p13) translocation resulting in a MECT1 – MAML2 fusion in which the CREB‐binding domain of the CREB coactivator MECT1 (also known as CRTC1, TORC1 or WAMTP1) is fused to the transactivation domain of the Notch coactivator MAML2. To gain further insights into the molecular pathogenesis of MECs, we cytogenetically and molecularly characterized a series of 29 MECs. A t(11;19) and/or an MECT1 – MAML2 fusion was detected in more than 55% of the tumors. Several cases with cryptic rearrangements that resulted in gene fusions were detected. In fusion‐negative MECs, the most common aberration was a single or multiple trisomies. Western blot and immunohistochemical studies demonstrated that the MECT1–MAML2 fusion protein was expressed in all MEC‐specific cell types. In addition, cotransfection experiments showed that the fusion protein colocalized with CREB in homogeneously distributed nuclear granules. Analyses of potential downstream targets of the fusion revealed differential expression of the cAMP/CREB ( FLT1 and NR4A2 ) and Notch ( HES1 and HES5 ) target genes in fusion‐positive and fusion‐negative MECs. Moreover, clinical follow‐up studies revealed that fusion‐positive patients had a significantly lower risk of local recurrence, metastases, or tumor‐related death compared to fusion‐negative patients ( P = 0.0012). When considering tumor‐related deaths only, the estimated median survival for fusion‐positive patients was greater than 10 years compared to 1.6 years for fusion‐negative patients. These findings suggest that molecularly classifying MECs on the basis of an MECT1 – MAML2 fusion is histopathologically and clinically relevant and that the fusion is a useful marker in predicting the biological behavior of MECs. © 2006 Wiley‐Liss, Inc.

Recent studies have shown that mucoepidermoid carcinomas (MECs) of the salivary and bronchial glands are characterized by a recurrent t(11;19)(q21;p13) translocation, resulting in a MECT1-MAML2 fusion in which the cAMP response element binding protein (CREB)-binding domain of the CREB-regulated transcriptional coactivator MECT1 (also known as CRTC1, WAMTP1, or TORC1) is fused to the transactivation domain of the Notch coactivator MAML2.1Tonon G Modi S Wu L Kubo A Coxon AB Komiya T O'Neil K Stover K El-Naggar A Griffin JD Kirsch IR Kaye FJ t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway.Nat Genet. 2003; 33: 208-213Crossref PubMed Scopus (190) Google Scholar,2Enlund F Behboudi A Andren Y Öberg C Lendahl U Mark J Stenman G Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors.Exp Cell Res. 2004; 292: 21-28Crossref PubMed Scopus (133) Google Scholar The molecular consequences of the fusion are still largely uncertain. Earlier studies have indicated that MECT1-MAML2 can activate Notch signaling independent of ligand stimulation,1Tonon G Modi S Wu L Kubo A Coxon AB Komiya T O'Neil K Stover K El-Naggar A Griffin JD Kirsch IR Kaye FJ t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway.Nat Genet. 2003; 33: 208-213Crossref PubMed Scopus (190) Google Scholar,2Enlund F Behboudi A Andren Y Öberg C Lendahl U Mark J Stenman G Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors.Exp Cell Res. 2004; 292: 21-28Crossref PubMed Scopus (133) Google Scholar and recent studies have demonstrated that MECT1-MAML2 can activate transcription of multiple cAMP/CREB target genes in vitro and that the N-terminal CREB-binding domain is crucial for the transforming activity of the fusion protein.3Coxon A Rozenblum E Park YS Joshi N Tsurutani J Dennis PA Kirsch IR Kaye FJ Mect1-Maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes.Cancer Res. 2005; 65: 7137-7144Crossref PubMed Scopus (112) Google Scholar,4Wu L Liu J Gao P Nakamura M Cao Y Shen H Griffin JD Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation.EMBO J. 2005; 24: 2391-2402Crossref PubMed Scopus (105) Google Scholar Collectively, these studies indicate that MECT1-MAML2 is a multifunctional protein with effects on several signaling pathways. Interestingly, recent studies have indicated that the MECT1-MAML2 fusion may not exclusively occur in MEC but may also be found in other types of glandular tumors. Thus, we have identified the fusion in two apparently unrelated benign tumor types: Warthin's tumor (WAT) and clear cell hidradenoma of the skin.2Enlund F Behboudi A Andren Y Öberg C Lendahl U Mark J Stenman G Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors.Exp Cell Res. 2004; 292: 21-28Crossref PubMed Scopus (133) Google Scholar,5Behboudi A Winnes M Gorunova L van den Oord JJ Mertens F Enlund F Stenman G Clear cell hidradenoma of the skin: a third tumor type with a t(11;19)-associated TORC1-MAML2 gene fusion.Genes Chromosomes Cancer. 2005; 43: 202-205Crossref PubMed Scopus (83) Google Scholar In this respect, MECT1-MAML2 is reminiscent of the ETV6-NTRK3 fusion that has been encountered in tumors originating from multiple cell lineages.6Lannon CL Sorensen PH ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages.Semin Cancer Biol. 2005; 15: 215-223Crossref PubMed Scopus (134) Google Scholar We read with interest the study by Martins et al7Martins C Cavaco B Tonon G Kaye FJ Soares J Fonseca I A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin's tumor of salivary glands.J Mol Diagn. 2004; 6: 205-210Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar in The Journal of Molecular Diagnostics in which they studied the MECT1-MAML2 fusion in 10 MECs and 7 WATs using fluorescence in situ hybridization (FISH) and/or reverse transcriptase-polymerase chain reaction. The fusion was detected in seven MECs but in none of the WATs. It should be noted that none of the classical WATs in this study had a t(11;19) translocation. However, one of their translocation- and fusion-positive MECs (case 10) was of particular interest because it was originally diagnosed and published as a benign WAT.8Martins C Fonseca I Roque L Soares J Cytogenetic characterization of Warthin's tumour.Oral Oncol Eur J Cancer. 1997; 33: 334-347Google Scholar This tumor was now reclassified as a MEC ex WAT. As indicated by the authors, it is known that MECs in rare instances may arise from or coexist with WAT. Case 10 in their series was suggested to represent such a case. The authors conclude that the MECT1-MAML2 fusion appears to be rare in WATs that do not contain concomitant evidence of MEC and that the fusion might be a useful diagnostic marker for MEC, especially in histologically challenging cases. The observations by Martins et al prompted us to re-examine our previously published t(11;19)- and fusion-positive WAT2Enlund F Behboudi A Andren Y Öberg C Lendahl U Mark J Stenman G Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors.Exp Cell Res. 2004; 292: 21-28Crossref PubMed Scopus (133) Google Scholar,9Mark J Dahlenfors R Stenman G Nordquist A A human adenolymphoma showing the chromosomal aberrations del (7)(p12p14-15) and t(11;19)(q21;p12-13).Anticancer Res. 1989; 9: 1565-1566PubMed Google Scholar both histologically and molecularly. Analysis of tissue sections from multiple levels of this tumor confirmed the original diagnosis of a benign WAT. Despite extensive sampling, we found no areas reminiscent of MEC in any of the sections examined. To further characterize this tumor, we also performed FISH on paraffin sections using a dual-color break-apart rearrangement probe for MAML2. Rearrangements of MAML2, indicating a MECT1-MAML2 fusion, were only detected in the morphologically benign tumor cells lining the duct-like structures and cysts of the tumor (Figure 1A). Split signals were not observed in the surrounding lymphoid cells, supporting the concept that these cells are non-neoplastic stromal cells. Immunostaining of the tumor using a MECT1-MAML2 polyclonal antibody10Behboudi A Enlund F Winnes M Andren Y Nordkvist A Leivo I Flaberg E Szekely L Makitie A Grenman R Mark J Stenman G Molecular classification of mucoepidermoid carcinomas: prognostic significance of the MECT1-MAML2 fusion oncogene.Genes Chromosomes Cancer. 2006; 45: 470-481Crossref PubMed Scopus (106) Google Scholar revealed nuclear staining of the benign tumor cells lining the duct-like structures and cysts, in agreement with the FISH results (Figure 1B). The surrounding lymphoid cells were mainly negative. Taken together, our results show that the present tumor represents a benign WAT with a MECT1-MAML2 gene fusion. Available data do, however, indicate that the fusion presumably is rare in WAT.7Martins C Cavaco B Tonon G Kaye FJ Soares J Fonseca I A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin's tumor of salivary glands.J Mol Diagn. 2004; 6: 205-210Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar In addition to the present case, there is only one previously reported WAT with a t(11;19)(q21;p13) translocation and one case with a possible variant translocation t(11;16)(q13–14;q23).11Bullerdiek J Haubrich J Meyer K Bartnitzke S Translocation t(11;19)(q21;p13.1) as the sole chromosome abnormality in a cystadenolymphoma (Warthin's tumor) of the parotid gland.Cancer Genet Cytogenet. 1988; 35: 129-132Abstract Full Text PDF PubMed Scopus (59) Google Scholar,12Nordkvist A Mark J Dahlenfors R Bende M Stenman G Cytogenetic observations in 13 cystadenolymphomas (Warthin's tumors).Cancer Genet Cytogenet. 1994; 76: 129-135Abstract Full Text PDF PubMed Scopus (22) Google Scholar The fact that the MECT1-MAML2 fusion may also infrequently occur in WAT is important to consider when using the fusion as a diagnostic marker for MEC. This is particularly important in metaplastic variants of WAT with atypia and mitotic activity, which may simulate MEC.13Simpson RHW Eveson JW Barnes L Eveson JW Reichart P Sidransky D Warthin tumour. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. IARC Press, Lyon, France2005: 263-265Google Scholar Our findings of the MECT1-MAML2 fusion in two unrelated benign tumor types are of particular interest in relation to recent data showing that MECT1-MAML2 preferentially occurs in low-grade MECs and that fusion-positive patients have a significantly lower risk of local recurrence, metastasis, or tumor-related death compared with fusion-negative patients.10Behboudi A Enlund F Winnes M Andren Y Nordkvist A Leivo I Flaberg E Szekely L Makitie A Grenman R Mark J Stenman G Molecular classification of mucoepidermoid carcinomas: prognostic significance of the MECT1-MAML2 fusion oncogene.Genes Chromosomes Cancer. 2006; 45: 470-481Crossref PubMed Scopus (106) Google Scholar When considering tumor-related deaths only, the estimated median survival for fusion-positive patients was found to be >10 years compared with 1.6 years for fusion-negative patients. Taken together, these observations suggest that the MECT1-MAML2 fusion is preferentially associated with benign and low-grade malignant tumors of glandular origin and that the fusion may be a useful marker in predicting the biological behavior of MECs.10Behboudi A Enlund F Winnes M Andren Y Nordkvist A Leivo I Flaberg E Szekely L Makitie A Grenman R Mark J Stenman G Molecular classification of mucoepidermoid carcinomas: prognostic significance of the MECT1-MAML2 fusion oncogene.Genes Chromosomes Cancer. 2006; 45: 470-481Crossref PubMed Scopus (106) Google Scholar Additional studies of larger series of tumors are, however, needed to further substantiate these observations. This study was supported by grants from the Swedish Cancer Society and the IngaBritt and Arne Lundberg Research Foundation. Winnes et al have previously reported the detection of MECT1-MAML2 expression in a case of Warthin's tumor (WAT),1Enlund F Behboudi A Andren Y Oberg C Lendahl U Mark J Stenman G Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors.Exp Cell Res. 2004; 292: 21-28Crossref PubMed Scopus (80) Google Scholar and in the present correspondence they have restated their confidence in the histological diagnosis of this case and propose that the MECT1-MAML2 fusion oncogene is not specific to mucoepidermoid-like (MEC-like) tumors. Although we cannot comment on the diagnosis of an isolated case of WAT based on a single photomicrograph, we would like to make two points to clarify what we believe to be the best interpretation of the emerging biology of MECT1-MAML2-associated tumorigenesis. First, we would like to emphasize that malignancies with a MEC-like histological pattern have been detected as primary lesions in a wide range of anatomical locations, including 1) each of the major and minor salivary glands, 2) the upper and lower respiratory tract, and 3) rare cases involving mandible, thyroid, breast, esophagus, stomach, pancreas, skin, and other sites.2Seifert G Sobin LH The World Health Organization's Histological Classification of Salivary Gland Tumors: a commentary on the second edition.Cancer. 1992; 70: 379-385Crossref PubMed Scopus (292) Google Scholar3Yih W Kratochvil FJ Stewart JC Intraoral minor salivary gland neoplasms: review of 213 cases.J Oral Maxillofac Surg. 2005; 63: 805-810Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar4Bhandarkar ND Chan J Strome M A rare case of mucoepidermoid carcinoma of the thyroid.Am J Otolaryngol. 2005; 26: 138-141Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar5Di Tommaso L Foschini MP Ragazzini T Magrini E Fornelli A Ellis IO Eusebi V Mucoepidermoid carcinoma of the breast.Virchows Arch. 2004; 444: 13-19Crossref PubMed Scopus (47) Google Scholar6Batoon SB Banzuela M Angeles HG Zoneraich S Maniego W Co J Primary mucoepidermoid carcinoma of the esophagus misclassified as adenocarcinoma on endoscopic biopsy.Am J Gastroenterol. 2000; 95: 2998-2999Crossref PubMed Google Scholar7Hayashi I Muto Y Fujii Y Morimatsu M Mucoepidermoid carcinoma of the stomach.J Surg Oncol. 1987; 34: 94-99Crossref PubMed Scopus (10) Google Scholar8Onoda N Kang SM Sugano S Yamashita Y Chung YS Sowa M Mucoepidermoid carcinoma of the pancreas: report of a case.Surg Today. 1995; 25: 843-877Crossref PubMed Scopus (27) Google Scholar9Riedlinger WF Hurley MY Dehner LP Lind AC Mucoepidermoid carcinoma of the skin: a distinct entity from adenosquamous carcinoma: a case study with a review of the literature.Am J Surg Pathol. 2005; 29: 131-135Crossref PubMed Scopus (42) Google Scholar Although the majority of these cases of MEC-like tumors have not yet been tested for the presence of MECT1-MAML2 gene expression, it is quite remarkable that identical MECT1-MAML2-positive cases have already been reported in tumors arising from parotid, submaxillary, oral, and many different thoracic sites within the bronchopulmonary tree.10Tonon G Modi S Wu L Kubo A Coxon AB Komiya T O'Neil K Stover K El-Naggar A Griffin JD Kirsch IR Kaye FJ t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway.Nat Genet. 2003; 33: 208-213Crossref PubMed Scopus (431) Google Scholar11Martins C Cavaco B Tonon G Kaye FJ Soares J Fonseca I A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin's tumor of salivary glands.J Mol Diagn. 2004; 6: 205-210Abstract Full Text Full Text PDF PubMed Google Scholar12Behboudi A Enlund F Winnes M Andren Y Nordkvist A Leivo I Flaberg E Szekely L Makitie A Grenman R Mark J Stenman G Molecular classification of mucoepidermoid carcinomas: prognostic significance of the MECT1-MAML2 fusion oncogene.Genes Chromosomes Cancer. 2006; 45: 470-481Crossref PubMed Scopus (250) Google Scholar In addition, we and others have noted the histological similarities between salivary MEC and certain cutaneous MEC-like tumors, which can include some cases of clear cell hidradenomas or eccrine acrospiroma.9Riedlinger WF Hurley MY Dehner LP Lind AC Mucoepidermoid carcinoma of the skin: a distinct entity from adenosquamous carcinoma: a case study with a review of the literature.Am J Surg Pathol. 2005; 29: 131-135Crossref PubMed Scopus (42) Google Scholar,13Fitzgibbon JF Googe PB Mucinous differentiation in adnexal sweat gland tumors.J Cutan Pathol. 1996; 23: 259-263Crossref PubMed Scopus (21) Google Scholar Therefore, the detection of the identical MECT1-MAML2 transcript in a cutaneous clear cell hidradenomas14Behboudi A Winnes M Gorunova L van den Oord JJ Mertens F Enlund F Stenman G Clear cell hidradenoma of the skin: a third tumor type with a t(11;19)-associated TORC1-MAML2 gene fusion.Genes Chromosomes Cancer. 2005; 43: 202-205Crossref PubMed Scopus (46) Google Scholar may suggest a common histological, genetic, or biological origin that serves to unify the concept of a MECT1-MAML2-associated tumorigenesis pathway. Second, we would like to suggest that the otherwise histogenetically distinct entity called WAT is not associated with MECT1-MAML2 gene expression. We base this conclusion on the absence of MECT1-MALML2 expression in seven different WATs cases11Martins C Cavaco B Tonon G Kaye FJ Soares J Fonseca I A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin's tumor of salivary glands.J Mol Diagn. 2004; 6: 205-210Abstract Full Text Full Text PDF PubMed Google Scholar and on the absence of MECT1-MAML2 in 26 different WATs in a separate study by Okabe et al.15Okabe M, Miyabe S, Nagatsuka H, Terada A, Hanai N, Yokoi M, Shimosato K, Eimoto T, Nakamura S, Nagai N, Hasegawa Y, Inagaki H: The MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma: a molecular and clinico-pathological study of 71 cases. Clin Cancer Res 2006, In pressGoogle Scholar Although it is partly semantic to argue the fine distinction between the reality of "no occurrence" versus "a very rare occurrence," we prefer the interpretation that an outlier sample of a MECT1-MAML2-positive non-MEC salivary gland tumor is more likely a case of misdiagnosis. This is particularly likely given the coincident presence of MEC and WAT within the same tumor samples.16Williamson JD Simmons BH El-Naggar AK Medeiros J Mucoepidermoid carcinoma involving Warthin tumor.Am J Clin Pathol. 2000; 114: 564-570Crossref PubMed Scopus (49) Google Scholar Finally, we agree that the ETV6-NTRK3 (EN) chimera represents an interesting example where the same EN fusion can result in either pediatric mesenchymal tumors or secretory breast cancer of adults and children.17Lannon CL Sorensen PH ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages.Semin Cancer Biol. 2005; 15: 215-223Crossref PubMed Scopus (67) Google Scholar Accordingly, it is possible that MECT1-MAML2 could also be associated with histologically dissimilar tumors. Although much remains to be learned about the biology of MECT1-MAML2 tumorigenesis, the emerging data to date suggest that MECT1-MAML2 is etiologically linked with a subset of MEC-like tumors and not with WAT.

Recent studies have shown that the t(11;19)(q21;p13) translocation in mucoepidermoid carcinomas and benign Warthin's tumors results in a fusion of the N-terminal CREB-binding domain of the cAMP coactivator TORC1 (a.k.a. MECT1 and WAMTP1) to the Notch coactivator MAML2. Here we show that a third tumor type, clear cell hidradenoma of the skin, also expresses this gene fusion. RT-PCR analysis of a clear cell hidradenoma with a t(11;19)(q21;p13) translocation revealed expression of a TORC1-MAML2 fusion transcript consisting of exon 1 of TORC1 fused to exons 2-5 of MAML2. Because the fusion was only detected in a single case, the frequency of this aberration in clear cell hidradenomas remains unknown. These results demonstrate that the t(11;19) in mucoepidermoid carcinoma, Warthin's tumor, and clear cell hidradenoma targets the same genes and results in identical gene fusions, indicating that at least subgroups of these glandular tumors evolve through activation of the same molecular pathways.