title: OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of spermatocytic seminoma reflecting distinct subpopulations of spermatogonia.
abstract: Spermatocytic seminoma (SS) is a rare testicular neoplasm that occurs predominantly in older men. In this study, we aimed to shed light on the histogenesis of SS by investigating the developmental expression of protein markers that identify distinct subpopulations of human spermatogonia in the normal adult testis. We analysed the expression pattern of OCT2, SSX2-4, and SAGE1 in 36 SS cases and four intratubular SS (ISS) as well as a series of normal testis samples throughout development. We describe for the first time two different types of SS characterized by OCT2 or SSX2-4 immunoexpression. These findings are consistent with the mutually exclusive antigenic profile of these markers during different stages of testicular development and in the normal adult testis. OCT2 was expressed predominantly in A(dark) spermatogonia, SSX2-4 was present in A(pale) and B spermatogonia and leptotene spermatocytes, whilst SAGE1 was exclusively present in a subset of post-pubertal germ cells, most likely B spermatogonia. The presence of OCT2 and SSX2-4 in distinct subsets of germ cells implies that these markers represent germ cells at different maturation stages. Analysis of SAGE1 and SSX2-4 in ISS showed spatial differences suggesting ongoing maturation of germ cells during progression of SS tumourigenesis. We conclude that the expression pattern of OCT2, SSX2-4, and SAGE1 supports the origin of SS from spermatogonia and provides new evidence for heterogeneity of this tumour, potentially linked either to the cellular origin of SS or to partial differentiation during tumour progression, including a hitherto unknown OCT2-positive variant of the tumour likely derived from A(dark) spermatogonia.
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Lim
authors.forename: Anne
authors.initials: A
authors.lastname: Goriely
authors.forename: Gareth Dh
authors.initials: GD
authors.lastname: Turner
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Ewen
authors.forename: Grete Krag
authors.initials: GK
authors.lastname: Jacobsen
authors.forename: Niels
authors.initials: N
authors.lastname: Graem
authors.forename: Andrew Om
authors.initials: AO
authors.lastname: Wilkie
authors.forename: Ewa
authors.initials: E
authors.lastname: Rajpert-De Meyts
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D018239:Seminoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013093:Spermatogonia / Q000378:metabolism* / Q000473:pathology; D013736:Testicular Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013737:Testis / Q000254:growth & development / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D012097:Repressor Proteins; C412325:SAGE1 protein, human; C491013:SLC22A2 protein, human; C093962:synovial sarcoma X breakpoint proteins; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)