title: Genomic and expression profiling of human spermatocytic seminomas: primary spermatocyte as tumorigenic precursor and DMRT1 as candidate chromosome 9 gene.
abstract: Spermatocytic seminomas are solid tumors found solely in the testis of predominantly elderly individuals. We investigated these tumors using a genome-wide analysis for structural and numerical chromosomal changes through conventional karyotyping, spectral karyotyping, and array comparative genomic hybridization using a 32 K genomic tiling-path resolution BAC platform (confirmed by in situ hybridization). Our panel of five spermatocytic seminomas showed a specific pattern of chromosomal imbalances, mainly numerical in nature (range, 3-24 per tumor). Gain of chromosome 9 was the only consistent anomaly, which in one case also involved amplification of the 9p21.3-pter region. Parallel chromosome level expression profiling as well as microarray expression analyses (Affymetrix U133 plus 2.0) was also done. Unsupervised cluster analysis showed that a profile containing transcriptional data on 373 genes (difference of > or = 3.0-fold) is suitable for distinguishing these tumors from seminomas/dysgerminomas. The diagnostic markers SSX2-4 and POU5F1 (OCT3/OCT4), previously identified by us, were among the top discriminatory genes, thereby validating the experimental set-up. In addition, novel discriminatory markers suitable for diagnostic purposes were identified, including Deleted in Azospermia (DAZ). Although the seminomas/dysgerminomas were characterized by expression of stem cell-specific genes (e.g., POU5F1, PROM1/CD133, and ZFP42), spermatocytic seminomas expressed multiple cancer testis antigens, including TSP50 and CTCFL (BORIS), as well as genes known to be expressed specifically during prophase meiosis I (TCFL5, CLGN, and LDHc). This is consistent with different cells of origin, the primordial germ cell and primary spermatocyte, respectively. Based on the region of amplification defined on 9p and the associated expression plus confirmatory immunohistochemistry, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for involvement in the development of spermatocytic seminomas.
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center/University Medical Center, Rotterdam, The Netherlands. l.looijenga@erasmusmc.nl
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
authors.forename: Remko
authors.initials: R
authors.lastname: Hersmus
authors.forename: Ad J M
authors.initials: AJ
authors.lastname: Gillis
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Stoop
authors.forename: Ruud J H L M
authors.initials: RJ
authors.lastname: van Gurp
authors.forename: Joris
authors.initials: J
authors.lastname: Veltman
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Ellen
authors.initials: E
authors.lastname: van Drunen
authors.forename: Ad Geurts
authors.initials: AG
authors.lastname: van Kessel
authors.forename: Renee Reijo
authors.initials: RR
authors.lastname: Pera
authors.forename: Dominik T
authors.initials: DT
authors.lastname: Schneider
authors.forename: Brenda
authors.initials: B
authors.lastname: Summersgill
authors.forename: Janet
authors.initials: J
authors.lastname: Shipley
authors.forename: Alan
authors.initials: A
authors.lastname: McIntyre
authors.forename: Peter
authors.initials: P
authors.lastname: van der Spek
authors.forename: Eric
authors.initials: E
authors.lastname: Schoenmakers
authors.forename: J Wolter
authors.initials: JW
authors.lastname: Oosterhuis
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D018239:Seminoma / Q000235:genetics* / Q000378:metabolism; D013090:Spermatocytes / Q000473:pathology; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C110547:DMRT1 protein; D014157:Transcription Factors