Whole-Exome Sequencing of Salivary Gland Mucoepidermoid Carcinoma

Abstract

Purpose-Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. To explore the genetic origins of MEC, we performed systematic genomic analyses of these tumors.Experimental Design-Whole-exome sequencing and gene copy number analyses were performed for 18 primary cancers with matched normal tissue. Fluorescence in situ hybridization (FISH) was used to determine the presence or absence of the MECT1-MAML2 translocation in 17 tumors.Results-TP53 was the most commonly mutated gene in MEC (28%), and mutations were found only in intermediate-and high-grade tumors. Tumors with TP53 mutations had more mutations overall than tumors without TP53 mutations (p=0.006). POU6F2 was the second most frequently mutated gene, found in three low-grade MECs with the same in-frame deletion. Somatic alterations in IRAK1, MAP3K9, ITGAL, ERBB4, OTOGL, KMT2C, and OBSCN were identified in at least two of the 18 tumors sequenced. FISH analysis confirmed the presence of the MECT1-MAML2 translocation in 15 of 17 tumors (88%).Conclusions-Through these integrated genomic analyses, MECT1-MAML2 translocation and somatic TP53 and POU6F2 mutations appear to be the main drivers of mucoepidermoid carcinoma.

CRTC1–MAML2 fusion in mucoepidermoid carcinoma of the breast

“…Although TP53 was frequently mutated in intermediate‐ and high‐grade MEC, none of the low‐grade tumours had TP53 mutations, with the only recurrent mutation in these tumours being POU6F2 (in three tumours). In addition, most tumours had a low mutational burden with many (six of nine) showing no copy number alterations . The breast MEC in our study lacked TP53 or PIK3CA mutations or complex copy number profiles typical of high‐grade triple‐negative carcinomas of no special type, and indeed showed no or only isolated genetic abnormalities aside from CRTC1 – MAML2 fusions.…”

“…SETD2 mutations have been rarely reported in breast tumours (at most ~3% of cases), notably only in luminal A cancers and phyllodes tumours but not in triple‐negative breast carcinomas . No SETD2 alterations have been reported to date in MEC of the salivary gland, and the significance of this isolated finding in one breast MEC is uncertain.…”

“…In contrast, acinic cell carcinomas arising in the breast harbour frequent TP53 mutations and complex patterns of copy number alterations which are not present in salivary gland acinic cell carcinomas, suggesting that these two tumours are not related despite their histological similarity . The molecular landscape of salivary gland MEC beyond CRTC1–MAML2 rearrangement has only been explored recently . Wang et al .…”

Heterogeneous impact of smoking on major salivary gland cancer according to histopathological subtype: A case‐control study

“…A recent study demonstrated that M‐SGCs have heterogeneous genetic features according to histopathologic subtype. For example, molecular cytogenetic analyses have identified recurring translocations as a key genomic event in MEC ( mucoepidermoid carcinoma translocated 1 [MECT1]‐mastermind-like gene family [MAML2] ) and AdCC ( MYB‐NF1B ) . Conversely, the most recent comprehensive genomic profiling of M‐SGC indicated that ADCA and salivary duct carcinoma (SDC) have diverse genomic mutations but not specific translocations .…”

Postoperative radiotherapy for T1/2N0M0 mucoepidermoid carcinoma positive for CRTC1/3‐MAML2 fusions

“…16,17 The fusion encodes a chimeric protein in which the Notch binding domain of MAML2 is replaced by the CREB binding, coiled-coil domain of CRTC1 fused to the transactivation domain of MAML2. 31 In this study, we retrospectively retrieved T1/2N0M0 mucoepidermoid carcinoma cases, none of which involved further treatment with PORT after complete tumor resection. 19 We and other research groups have shown that CRTC1/3-MAML2 fusions are highly specific to mucoepidermoid carcinoma, they are not detected in any other type of salivary carcinoma, [16][17][18][19][20] and that the fusions are objective markers associated with a tumor subset with lower grade histology, less advanced clinical stage, lower incidence of lymph node metastasis, and a favorable clinical course for the patient.…”