Recurrent rearrangements of the Myb/SANT-like DNA-binding domain containing 3 gene (MSANTD3) in salivary gland acinic cell carcinoma

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.

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“…The role of myb/SANT‐like DNA‐binding domain‐containing protein 3‐like, which was strongly expanded from 6 to 39 in the B. germanica genome, is not conclusively resolved. However, it also appears to regulate gene expression and protein synthesis in mammals (Barasch et al., ).…”

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“…Animal models and immunohistochemical studies have suggested that an upregulated mTOR pathway may be involved in the development of AcCCs . A 2017 study demonstrated recurrent rearrangements involving the Myb/SANT‐like DNA binding domain containing 3 ( MSANTD3 ) gene on chromosome 9q in 3 of 20 cases of AcCC …”

“…76,77 A 2017 study demonstrated recurrent rearrangements involving the Myb/SANT-like DNA binding domain containing 3 (MSANTD3) gene on chromosome 9q in 3 of 20 cases of AcCC. 78 On FNAC, smears are highly cellular and consist of clusters of cells with slightly enlarged, eccentrically located nuclei, evenly distributed chromatin, and occasionally conspicuous nucleoli with abundant cytoplasm demonstrating coarse zymogen granules (Figure 7). Occasional stripped nuclei are common.…”

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“…In PAC of classic type, the E710D hotspot mutation in exon 15 of the PRKD1 gene is unique to this tumor type, rearrangement of the PRKD1 ‐ 3 genes are described exclusively in PAC of cribriform type, and the HTN3 ‐ MSANTD3 fusion in acinic cell carcinoma has not been described in any other tumor type (Fig. D; ).…”

“…In PAC of classic type, the E710D hotspot mutation in exon 15 of the PRKD1 gene is unique to this tumor type, rearrangement of the PRKD1-3 genes are described exclusively in PAC of cribriform type, and the HTN3-MSANTD3 fusion in acinic cell carcinoma has not been described in any other tumor type ( Fig. 2D; [35][36][37]. The most promising venues for targeted therapy is in SC which consistently harbor fusions involving ETV6, with the most frequent fusion partner being NTRK3, and RET in a subset of cases ( Fig.…”