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.
Highlights
Adult male germ cell tumors (GCTs) are the most commonly diagnosed solid tumors in men ages 18 to 35 years [1]
We identified a 200-kb coordinately regulated region at 12p13.31 that was overexpressed in embryonal carcinomas and seminomas, which consisted of several stem cell–associated genes
Genes from other chromosomes clearly play a role in GCT etiology and progression, the importance of the gain of 12p is further exemplified by the overrepresentation of overexpressed transcripts from 12p compared with overexpressed transcripts from all other chromosomes by Fisher’s exact test (P < 0.001), consistent with previous findings [30]
Summary
Adult male germ cell tumors (GCTs) are the most commonly diagnosed solid tumors in men ages 18 to 35 years [1]. Nonseminomatous GCTs are further subdivided into embryonal carcinomas, which show early zygotic or embryonal-like differentiation, yolk sac tumors and choriocarcinomas, which exhibit extraembryonal forms of differentiation, and teratomas, which show somatic differentiation along multiple lineages [3]. Both seminomas and embryonal carcinoma are known to express stem cell markers, such as POU5F1 [4] and NANOG [5]
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