title: Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors.
abstract: Adult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray ( approximately 83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell-associated genes in embryonal carcinoma, including several core "stemness" genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas.
authors.affiliation: Cell Biology Program and Departments of Medicine, Epidemiology and Biostatistics, and Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Korkola
authors.forename: Jane
authors.initials: J
authors.lastname: Houldsworth
authors.forename: Rajendrakumar S V
authors.initials: RS
authors.lastname: Chadalavada
authors.forename: Adam B
authors.initials: AB
authors.lastname: Olshen
authors.forename: Debbie
authors.initials: D
authors.lastname: Dobrzynski
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: George J
authors.initials: GJ
authors.lastname: Bosl
authors.forename: R S K
authors.initials: RS
authors.lastname: Chaganti
mesh_terms: D018236:Carcinoma, Embryonal / Q000235:genetics / Q000503:physiopathology; D049109:Cell Proliferation; D002881:Chromosomes, Human, Pair 12; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D005810:Multigene Family; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D039904:Pluripotent Stem Cells / Q000502:physiology*; D000091402:Prohibitins; D018239:Seminoma / Q000235:genetics / Q000503:physiopathology; D013736:Testicular Neoplasms / Q000235:genetics* / Q000503:physiopathology