Abstract
Pathogenic gene fusions have been identified in several histologic types of salivary gland neoplasia, but not previously in acinic cell carcinoma (AcCC). To discover novel gene fusions, we performed whole-transcriptome sequencing surveys of three AcCC archival cases. In one specimen we identified a novel HTN3-MSANTD3 gene fusion, and in another a novel PRB3-ZNF217 gene fusion. The structure of both fusions was consistent with the promoter of the 5’ partner (HTN3 or PRB3), both highly expressed salivary gland genes, driving overexpression of full-length MSANTD3 or ZNF217. By fluorescence in situ hybridization of an expanded AcCC case series, we observed MSANTD3 rearrangements altogether in 3 of 20 evaluable cases (15%), but found no additional ZNF217 rearrangements. MSANTD3 encodes a previously uncharacterized Myb/SANT domain-containing protein. Immunohistochemical staining demonstrated diffuse nuclear MSANTD3 expression in 8 of 27 AcCC cases (30%), including the three cases with MSANTD3 rearrangement. MSANTD3 displayed heterogeneous expression in normal salivary ductal epithelium, as well as among other histologic types of salivary gland cancer though without evidence of translocation. In a broader survey, MSANTD3 showed variable expression across a wide range of normal and neoplastic human tissue specimens. In preliminary functional studies, engineered MSANTD3 overexpression in rodent salivary gland epithelial cells did not enhance cell proliferation, but led to significant upregulation of gene sets involved in protein synthesis. Our findings newly identify MSANTD3 rearrangement as a recurrent event in salivary gland AcCC, providing new insight into disease pathogenesis, and identifying a putative novel human oncogene.
Highlights
In cancers, chromosomal translocations and rearrangements can create gene fusions, resulting in the effective overexpression of full-length cancer genes or producing chimeric oncoproteins [1, 2]
Transcriptome sequencing identifies novel gene fusions in acinic cell carcinoma As part of a broader transcriptome survey to discover novel oncogenic gene fusions or mutations in less common cancer diagnoses that are available mainly as archived formalin-fixed paraffin-embedded (FFPE) tissue blocks [14], here we carried out whole-transcriptome sequencing of three prototypic AcCC cases
The first novel chimeric transcript resulted from fusion of noncoding exon 1of Histatin 3 (HTN3; cytoband 4q13.3) to exon 2 of Myb/SANT-like DNA-binding domain contain 3 (MSANTD3; cytoband 9q31.1) (Fig 1A)
Summary
Chromosomal translocations and rearrangements can create gene fusions, resulting in the effective overexpression of full-length cancer genes or producing chimeric oncoproteins [1, 2]. Recurrent gene fusions have been identified in several different salivary gland neoplasms [6,7,8], including PLAG1 fusions (most often CTNNB1-PLAG1) and HMGA2 rearrangements in pleomorphic adenoma, CRTC1-MAML2 fusion in mucoepidermoid carcinoma, MYB-NFIB (or MYBL1-NFIB [9, 10]) fusion in adenoid cystic carcinoma, ETV6-NTRK3 fusion in mammary analogue secretory carcinoma of the salivary gland, and EWSR1-ATF1 fusion in hyalinizing clear cell carcinoma These fusions, impacting cell signaling pathways and cell-cycle regulation, inform neoplastic mechanisms, provide molecular biomarkers for refined diagnosis, and may suggest new opportunities for therapy. Whether other salivary gland neoplasms harbor recurrent gene fusions has remained an open question
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