X-INACTIVATION IN HUMAN TESTICULAR-TUMORS - XIST-EXPRESSION AND ANDROGEN RECEPTOR METHYLATION STATUS

In female mammalian cells, inactivation of one of the X chromosomes co mpensates the increased dosage of X-linked genes as compared with thei r male counterparts, This process is initiated by the X-inactive speci fic transcripts of the xist/XIST gene in cis, resulting in methylation of specific sites of genes to be silenced. However, in male germ cell s, X inactivation is established by xist/XIST expression only, We inve stigated the X inactivation pattern in human testicular tumors of diff erent histogenesis by analysis of XIST expression and methylation of t he androgen receptor gene. XIST was expressed only in tumors derived f rom the germ cell lineage with supernumerical X chromosomes: seminomas , nonseminomas, and spermatocytic seminomas, Although low expression w as present in testicular parenchyma with spermatogenesis, XIST was exp ressed at a higher level in parenchyma with carcinoma ia situ, the pre cursor lesion of seminomas and nonseminomas. Despite the consistent ex pression of XIST in germ-cell-derived tumors with gain of X chromosome s, methylation of the androgen receptor gene was present in all differ entiated but only in a proportion of the undifferentiated nonseminomas , This differential pattern of methylation was also found in a number of representative cell lines. Our data indicate that the counting mech anism resulting in X inactivation is functional in testicular cancers of different histogenesis. Moreover, the differentiation-dependent pat tern of X inactivation as reported during normal development Ln the ca se of multiple X chromosomes by methylation is retained in these tumor s. We conclude therefore that X inactivation allows the excessive gain of X chromosomes found in germ-cell-derived tumors of the adult testi s, In addition, this offers an interesting model to study the fundamen tal mechanisms of these processes.