Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

Abstract

Mucoepidermoid carcinoma is the most common salivary gland malignancy, and includes a spectrum of lesions ranging from non-aggressive low-grade tumors to aggressive high-grade tumors. To further characterize this heterogeneous group of tumors we have performed a comprehensive analysis of copy number alterations and CRTC1-MAML2 fusion status in a series of 28 mucoepidermoid carcinomas. The CRTC1-MAML2 fusion was detected by RT-PCR or fluorescence in situ hybridization in 18 of 28 mucoepidermoid carcinomas (64%). All 15 low-grade tumors were fusion-positive whereas only 3 of 13 high-grade tumors were fusion-positive. Highresolution array-based comparative genomic hybridization revealed that fusion-positive tumors had significantly fewer copy number alterations/tumor compared with fusion-negative tumors (1.5 vs 9.5; P ¼ 0.002). Twelve of 18 fusion-positive tumors had normal genomic profiles whereas only 1 out of 10 fusionnegative tumors lacked copy number alterations. The profiles of fusion-positive and fusion-negative tumors were very similar to those of low-and high-grade tumors. Thus, low-grade mucoepidermoid carcinomas had significantly fewer copy number alterations/tumor compared with high-grade mucoepidermoid carcinomas (0.7 vs 8.6; Po0.0001). The most frequent copy number alterations detected were losses of 18q12.2-qter (including the tumor suppressor genes DCC, SMAD4, and GALR1), 9p21.3 (including the tumor suppressor genes CDKN2A/B), 6q22.1-q23.1, and 8pter-p12.1, and gains of 8q24.3 (including the oncogene MAFA), 11q12.3-q13.2, 3q26.1-q28, 19p13.2-p13.11, and 8q11.1-q12.2 (including the oncogenes LYN, MOS, and PLAG1). On the basis of these results we propose that mucoepidermoid carcinoma may be subdivided in (i) low-grade, fusion-positive mucoepidermoid carcinomas with no or few genomic imbalances and favorable prognosis, (ii) high-grade, fusion-positive mucoepidermoid carcinomas with multiple genomic imbalances and unfavorable prognosis, and (iii) a heterogeneous group of high-grade, fusion-negative adenocarcinomas with multiple genomic imbalances and unfavorable outcome. Taken together, our studies indicate that molecular genetic analysis can be a useful adjunct to histologic scoring of mucoepidermoid carcinoma and may lead to development of new clinical guidelines for management of these patients.

Molecular Heterogeneity in Mucoepidermoid Carcinoma: Conceptual and Practical Implications

“…In that context, fusion positive MEC, regardless of grade, manifest a more stable genome and better clinical behaviour, while fusion negative MEC represent a distinctly different pathway characterized by marked genomic instability and relatively aggressive tumors. This contention is supported by our recent findings and those of others [20], where fusion positive tumors showed considerably lower copy number alterations than fusion negative MECs.…”

“…A recent genome wide comprehensive analysis of copy number alterations of MEC has reported that low-grade tumors were fusion positive whereas only 3 of 13 highgrade tumors were fusion positive [20]. The analysis revealed that fusion-positive tumors had significantly fewer copy number alterations (CNAs) compared with fusionnegative tumors (1.5 vs. 9.5; p 0.002).…”

“…The most frequent CNAs detected were losses at 18q12.2-qter (including tumor suppressor genes DCC, SMAD4 and GALR1), 9p21.3 (including tumor suppressor genes CDKN2A/B), 6q22.1-q23.1, and 8pter-p12.1, and gains of 8q24.3 (including oncogene MAFA), 11q12.3-q13.2, 3q26.1-q28, 19p13.2-p13.11, and 8q11.1-q12.2 (including the oncogenes LYN, MOS, and PLAG1). Based on these results it was proposed that MEC may be subdivided in (1) low-grade, fusionpositive MEC with no or few genomic imbalances and favorable prognosis, (2) high-grade, fusion-positive MEC with multiple genomic imbalances and unfavorable prognosis, and (3) a heterogeneous group of high-grade, fusion-negative adenocarcinomas with multiple genomic imbalances and unfavorable outcomes [20]. This study opens a new avenue, indicating that molecular genetic analysis can be useful adjunct to histologic scoring of MEC and may lead to development of new clinical guidelines for the management of these patients [20].…”

“…Based on these results it was proposed that MEC may be subdivided in (1) low-grade, fusionpositive MEC with no or few genomic imbalances and favorable prognosis, (2) high-grade, fusion-positive MEC with multiple genomic imbalances and unfavorable prognosis, and (3) a heterogeneous group of high-grade, fusion-negative adenocarcinomas with multiple genomic imbalances and unfavorable outcomes [20]. This study opens a new avenue, indicating that molecular genetic analysis can be useful adjunct to histologic scoring of MEC and may lead to development of new clinical guidelines for the management of these patients [20].…”

Fusion Oncogenes in Salivary Gland Tumors: Molecular and Clinical Consequences

“…therein]. Based on a recent arrayCGH study of genomic imbalances in fusion-positive and fusion-negative MECs, we proposed that MEC may be subdivided in (a) low-grade, fusion-positive tumors with no or few genomic imbalances and favorable prognosis, (b) highgrade, fusion-positive tumors with multiple genomic imbalances (including deletions of the tumor suppressor gene CDKN2A) and unfavorable prognosis, and (c) a heterogeneous group of high-grade, fusion-negative non-MEC adenocarcinomas with multiple genomic imbalances and unfavorable outcome [40]. There is sufficient evidence at hand indicating that the CRTC1-MAML2 fusion is a clinically useful biomarker that distinguishes true MECs, most of which have an excellent prognosis, from fusion-negative MEC-like tumors with a more unfavorable prognosis.…”