X inactivation in human testicular tumors. XIST expression and androgen receptor methylation status.
In female mammalian cells, inactivation of one of the X chromosomes compensates the increased dosage of X-linked genes as compared with their male counterparts. This process is initiated by the X-inactive specific transcripts of the xist/XIST gene in cis, resulting in methylation of specific sites of genes to be silenced. However, in male germ cells, X inactivation is established by xist/XIST expression only. We investigated the X inactivation pattern in human testicular tumors of different histogenesis by analysis of XIST expression and methylation of the androgen receptor gene. XIST was expressed only in tumors derived from the germ cell lineage with supernumerical X chromosomes: seminomas, nonseminomas, and spermatocytic seminomas. Although low expression was present in testicular parenchyma with spermatogenesis, XIST was expressed at a higher level in parenchyma with carcinoma in situ, the precursor lesion of seminomas and nonseminomas. Despite the consistent expression of XIST in germ-cell-derived tumors with gain of X chromosomes, methylation of the androgen receptor gene was present in all differentiated 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 mechanism resulting in X inactivation is functional in testicular cancers of different histogenesis. Moreover, the differentiation-dependent pattern of X inactivation as reported during normal development in the case of multiple X chromosomes by methylation is retained in these tumors. We conclude therefore that X inactivation allows the excessive gain of X chromosomes found in germ-cell-derived tumors of the adult testis. In addition, this offers an interesting model to study the fundamental mechanisms of these processes.
Looijenga
L H
LH
Laboratory for Experimental Patho-Oncology, Dr. Daniel den Hoed Cancer Center, Academic Hospital Rotterdam, The Netherlands.
Gillis
A J
AJ
van Gurp
R J
RJ
Verkerk
A J
AJ
Oosterhuis
J W
JW
D000328:Adult; D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008745:Methylation; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D011944:Receptors, Androgen / Q000378:metabolism*; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014960:X Chromosome
D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D011944:Receptors, Androgen; D014157:Transcription Factors; C077885:XIST non-coding RNA