Novel epigenetically deregulated genes in testicular cancer include homeobox genes andSCGB3A1(HIN-1)


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Abstract

Testicular germ cell tumours (TGCTs) are classified into two main histological subgroups: seminomas and non-seminomas. The latter comprise several subtypes: embryonal carcinomas, yolk sac tumours, choriocarcinomas, and teratomas. These embryonal and extra-embryonal-like differentiation lineages represent a caricature of early normal development, and inactivation of gene expression through promoter hypermethylation may therefore be of particular importance in germ cell tumourigenesis. The promoter methylation status of ten candidate genes—CDH13, DLX6, EMX2, HOXA9, HOXB5, MSX1, MSX2, RASSF1A, RUNX3, andSCGB3A1(aliasHIN-1)—was assessed by methylation-specific PCR in seven intratubular germ cell neoplasias and 55 primary TGCTs. Furthermore, by a discovery-based global approach, comparing cDNA microarray expression profiles of two germ cell tumour cell lines before and after treatment with the demethylating agent 5-aza-2′-deoxycytidine, a gene list of potentially epigenetic targets was identified, from whichCGGBP1, CGRRF1, SMARCC2, SORBS1, andXPAwere analysed further. Overall, the non-seminomas were significantly more often methylated than were seminomas (p< 0.001). The three most frequently methylated genes among this subtype wereSCGB3A1(54%),RASSF1A(29%), andHOXA9(26%).CDH13andHOXB5were methylated at low frequencies (10–15%), andEMX2, MSX1, RUNX3, SORBS1, andXPAonly rarely (<10%). In conclusion, this study has identified several novel epigenetically deregulated target genes in TGCT development, including homeobox genes andSCGB3A1, suggesting that epigenetic inactivation of key genes in normal development also has an important role in TGCTs.

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