Clinicopathological significance of MAML2 gene split in mucoepidermoid carcinoma

Abstract

CRTC1-MAML2 and CRTC3-MAML2 fusions have been associated with favorable clinicopathological features of mucoepidermoid carcinomas. However, the significance of the MAML2 gene split has not been fully clarified. In the present study, 95 mucoepidermoid carcinomas (paraffin-embedded materials) were analyzed for CRTC1-MAML2 and CRTC3-MAML2 fusions by RT-PCR and for the MAML2 gene split by FISH. Quantitative RT-PCR for the CRTC1-MAML2 transcript was performed in selected cases. MLL gene involvement, which has been reported in some leukemia cases, was examined by FISH in fusion partner-unknown cases. CRTC1-MAML2 and CRTC3-MAML2 fusions were detected in 37 and 6 cases, respectively. The MAML2 gene split was detected in 62 cases, which included all CRTC1/3-MAML2 fusion-positive cases. The level of CRTC1-MAML2 transcript expression was highly variable, and its clinicopathological impact was unclear. The MLL gene split was not detected. Mucoepidermoid carcinomas negative for CRTC1/3-MAML2 and positive for the MAML2 gene split (n = 19) showed favorable clinicopathological tumor features similar to those positive for CRTC1/3-MAML2 fusions. Compared with negative cases (n = 33), mucoepidermoid carcinomas positive for the MAML2 split (n = 62) were associated with lower patient age, a mild female predilection, a smaller tumor size, less frequent nodal metastasis, a lower clinical stage, a lower histological grade, and longer overall and disease-free survival. The MAML2 gene split emerged as an independent prognostic factor for both overall and disease-free survival in multivariate prognostic analysis. The presence of the MAML2 gene split defines a distinct mucoepidermoid carcinoma subset that is associated clinicopathologically with favorable tumor features. (Cancer Sci 2013; 104: 85-92) M ucoepidermoid carcinomas represent 5% of all salivary gland tumors and 20% of salivary malignancies.(1,2) A subset of these carcinomas has been associated with a recurring chromosomal translocation, t(11;19)(q21;p13), which generates a fusion protein composed of the N-terminal of cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1), also called MECT1, TORC1 or WAMP1, and the C-terminal of mastermind-like gene 2 (MAML2).(3-6) Recent data suggest that CRTC1-MAML2 induced-activation of CREB is critical for cell transformation.(5,6) CTCR1-MAML2 fusion has been detected in 40-80% of primary salivary gland mucoepidermoid carcinomas, and we and other research groups have shown that the fusion gene is associated with a distinct tumor subset with an indolent clinical course. and in Nakayama et al. (12) we reveal that CRTC3-MAML2 fusion-positive mucoepidermoid carcinoma cases have an excellent prognosis. These findings suggest that both CRTC1-MAML2 and CRTC3-MAML2 fusions may be associated with mucoepidermoid carcinoma cases with favorable clinicopathological tumor features. (13) CRTC1/3-MAML2 fusions have been detected using an RT-PCR technique, assuming that exon 1 of CRTC1/3 genes is fused to exons 2-5 of th...

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

“…The protein binds to an extended groove that is formed by the interaction of CBF1, suppressor of Hairless, LAG‐1 with ICN, which could positively regulate the Notch signalling pathway 34, 35. In fact, the translocation of MAML2 could create a fusion oncogene MECT1 / MAML2 , which could be involved in the process of disrupting the normal cell cycle, differentiation and tumour development, exerting an oncogenic role in mucoepidermoid carcinoma 36. Recently, the oncogenic CRCT3 ‐ MAML2 fusion was also identified to be associated with a better survival of patients with mucoepidermoid carcinoma 37.…”

Thyroid sclerosing mucoepidermoid carcinoma with eosinophilia distinct from the salivary type

“…MAML2 rearrangement is observed in more than half of salivary MEC cases, is specific for salivary MEC, and predicts a favorable prognosis [24][25][26][27]. However, MAML2 by FISH was intact in all three of our cases.…”

Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma

“…MAML2 is located at 11q21, and its encoding protein is capable of forming a multiprotein complex with NIC-RBPJκ, which is an essential step for the Notch-mediated transcriptional activation (33). The oncogenic role of MAML2 was first described in mucoepidermoid carcinoma, in which translocation of MAML2 in mucoepidermoid carcinoma will create a fusion oncogene mucoepidermoid carcinoma translocated 1 (MECT1)—MAML2 that is involved in disrupting the normal cell cycle, differentiation, and tumor development (34). Clinical investigation also demonstrated that mucoepidermoid carcinoma patients with a positive MECT1–MAML2 fusion and MAML2 gene split had significantly longer OS (34, 35).…”

“…The oncogenic role of MAML2 was first described in mucoepidermoid carcinoma, in which translocation of MAML2 in mucoepidermoid carcinoma will create a fusion oncogene mucoepidermoid carcinoma translocated 1 (MECT1)—MAML2 that is involved in disrupting the normal cell cycle, differentiation, and tumor development (34). Clinical investigation also demonstrated that mucoepidermoid carcinoma patients with a positive MECT1–MAML2 fusion and MAML2 gene split had significantly longer OS (34, 35). It was reported that MECT1–MAML2 could bind to and activate both c-jun and c-fos, which are known as proto-oncogenes (36).…”