Whole-Genome Sequencing of Common Salivary Gland Carcinomas: Subtype-Restricted and Shared Genetic Alterations

Abstract

Salivary gland carcinomas (SGCs) are uncommon malignancies that are comprised of widely variable histopathologic subtypes, of which adenoid cystic, mucoepidermoid, and salivary duct carcinomas are the most often clinically encountered. Each of these SGC subtypes manifests distinctly different phenotypic, clinical, and molecular characteristics that reflect remarkable inter-tumor heterogeneity. Although the primary treatment for salivary tumors is surgery, patients with unresectable primary, recurrent, and metastatic disease have limited therapeutic options. We conducted whole genomic sequencing to characterize the molecular genetic events that are associated with the evolution, diversity, and progression of these uncommon salivary malignancies. Our whole genomic sequencing identified type-specific and shared genetic alterations to be associated with early phenotypic commitment and progression and delineated intra-subtype heterogeneity and potential molecular targets of biologic and therapeutic utilities to be validated.Research Medical Library, MD Anderson Cancer Center (Houston, TX), for detailed editing and constructive modification of the manuscript.Research.

Recurrent IDH2 Mutations in Salivary Gland Striated Duct Adenoma Define an Expanded Histologic Spectrum Distinct From Canalicular Adenoma

“…Our findings demonstrate that salivary SDA is another tumor type with recurrent IDH2 mutations. IDH2 mutations have never previously been identified as either a defining molecular feature or even a rare event in large molecular profiling studies of most common salivary gland malignancies 26–41. As such, this finding represents the first role for IDH2 in salivary gland tumors.…”

“…IDH2 mutations have never previously been identified as either a defining molecular feature or even a rare event in large molecular profiling studies of most common salivary gland malignancies. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] As such, this finding represents the first role for IDH2 in salivary gland tumors. FIGURE 2.…”

Notch signaling pathway: architecture, disease, and therapeutics

“…Other cancers. Adenoid cystic carcinoma (ACC), commonly found in the salivary gland, frequently features activating NOTCH1 and NOTCH2 mutations [415][416][417][418] . NOTCH1 inhibitors have significant antitumor efficacy in both ACC patients and patient-derived xenograft (PDX) models 419,420 .…”

The Therapeutic Landscape of Salivary Gland Malignancies—Where Are We Now?

“…Novel treatment options, combined with Notch inhibitors, are therefore needed in this clinically poor group. In addition, multiple research groups are focusing on molecular abnormalities (DNA as well as RNA) which may be of use for SGMs [ 154 , 155 , 156 , 157 , 158 , 159 , 160 ]. Selecting patients based on the tumor molecular profile can be considered a major advantage and should be recommended as this can guide the development of novel therapeutic strategies according to disease biology and further personalize patient treatment.…”