LAUSR

Objective Salivary adenoid cystic carcinoma(SACC) is identified as a tumor with biphasic differentiation of epithelial and myoepithelial cells, showing tubular, cribriform and solid subtypes. The solid subtype is considered as high-grade with more aggressiveness and poorer prognosis. However, the molecular mechanism remains unknown. The aim of this study was to identify the clinicopathological characteristics of high-grade SACC, to clarify the molecular mechanism underline its distinct characteristics, and hopefully to explore potential molecular targets for SACC therapy. Study design Activated Notch1 (NICD) and myoepithelial cell markers were used for immunohistochemistry in 119 SACCs including 59 cribriform-tubular and 60 solid subtypes. Notch1 mutations were analyzed by DNA sequencing in all the SACC cases. The effect of activating NOTCH pathway on the biological behavior of SACC cell lines was investigated with transfection and functional studies. Results Notch1 mutations in the negative regulatory region and Pro-Glu-Ser-Thr–rich domains were identified in 26 of 119 patients with SACC, and 24 (92%) of 26 Notch1 mutant cases were predicted to be activating with NICD positive, with 2 cases predicted to be inactivating with NICD negative. Most (23/24, 96%) cases with activating Notch1 mutations were high-grade solid SACCs. Meantime, only 17 (18%) of 93 NOTCH1 wild-type tumors stained positive, and 16 of 17 tumors with NICD positive were high-grade solid subtypes. Furthermore, high-grade solid SACCs showed dramatically decreased short-term survival, tended to suffer bone invasion and metastasis, and presented NICD positive and myoepithelial cell markers negative simultaneously. Transfection and functional studies showed forced NICD expression promoted high level of proliferation and migration in SACC cells. Conclusions Our findings showed activating Notch1 mutations were related to the loss of myoepithelial differentiation in high-grade SACCs and might contribute to higher proliferation and worse outcome in high-grade tumors. Targeting the Notch signaling pathway in high-grade SACCs may provide therapeutic benefits.