Aberrant expression of cyclin D2 is an early event in human male germ cell tumorigenesis.

Human male germ cell tumors (GCTs) arise in the spermatocytic lineage, and subsets display embryonal-like differentiation. Virtually all GCTs exhibit multiple copies of the short arm of chromosome 12, even in carcinoma in situ/intratubular germ cell neoplasia, the earliest recognizable neoplastic lesion of germ cells. Among the candidate amplified genes mapped to 12p, expression of the cyclin D2 gene (CCND2) was deregulated in a panel of GCT cell lines, with the relative level of steady-state mRNA and protein inversely correlated with the pattern of differentiation characteristic of the cell line. GCT cell lines with a more differentiated phenotype, as indicated by an immunophenotypic analysis, displayed lower cyclin D2 expression with a concurrent increase in expression of the cell cycle inhibitor p21. In the GCT cell lines in which cyclin D2 was highly expressed, cyclin D2 was in complex with its expected catalytic partners (Cdk4 and Cdk6). Whereas no detectable cyclin D2 expression was evident in normal human germ cells, cyclin D2 was expressed in the abnormal germ cells of all carcinoma in situ/intratubular germ cell neoplasia lesions studied. In GCT specimens that displayed no evidence of differentiation (seminoma) or primitive differentiation (embryonal carcinoma), cyclin D2 expression was detected. However, in tumor specimens with certain patterns of differentiation (teratoma and yolk sac tumor), expression was down- or up-regulated depending on the pattern. Our data suggest that aberrant cyclin D2 expression is an early event in germ cell tumorigenesis.