Date Published: February 17, 2017
Publisher: Public Library of Science
Author(s): Nicholas Barasch, Xue Gong, Kevin A. Kwei, Sushama Varma, Jewison Biscocho, Kunbin Qu, Nan Xiao, Joseph S. Lipsick, Robert J. Pelham, Robert B. West, Jonathan R. Pollack, Chandan Kumar-Sinha.
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.
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]. Gene fusions were originally considered hallmarks of hematopoietic and mesenchymal cancers, but more recently have been reported in a wide range of epithelial cancer types . Identifying and characterizing gene fusions have provided new molecular insight into disease pathogenesis. Moreover, gene fusions have refined the diagnosis and classification of cancers, and have proven to be effective targets for molecularly-directed therapy. Examples include the classic BCR-ABL fusion in chronic myelogenous leukemia , and more recently, EML4-ALK in lung cancer .
Recurrent chromosomal rearrangements (and the resultant gene fusions) are known to characterize other salivary gland tumors, but have not previously been reported in AcCC. Here, by whole-transcriptome profiling of three AcCC cases, we discovered two novel fusion genes, HTN-MSANTD3 and PRB3-ZNF217, and found that MSANTD3 locus rearrangements are recurrent events observed in approximately 15% of AcCC cases. Furthermore, in a cell line model, MSANTD3 overexpression led to the upregulation of genes involved in protein synthesis, a cellular process often upregulated in cancer .