title: 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.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Barasch
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Xue
authors.initials: X
authors.lastname: Gong
authors.affiliation: Genomic Health, Redwood City, California, United States of America.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Kwei
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Sushama
authors.initials: S
authors.lastname: Varma
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Jewison
authors.initials: J
authors.lastname: Biscocho
authors.affiliation: Genomic Health, Redwood City, California, United States of America.
authors.forename: Kunbin
authors.initials: K
authors.lastname: Qu
authors.affiliation: Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, California, United States of America.
authors.forename: Nan
authors.initials: N
authors.lastname: Xiao
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Lipsick
authors.affiliation: Genomic Health, Redwood City, California, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pelham
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000818:Animals; D018267:Carcinoma, Acinar Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D020869:Gene Expression Profiling; D050939:Gene Fusion; D015321:Gene Rearrangement; D006801:Humans; D051381:Rats; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502333:CNPY2 protein, human