title: Novel epigenetically deregulated genes in testicular cancer include homeobox genes and SCGB3A1 (HIN-1).
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, and SCGB3A1 (alias HIN-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 which CGGBP1, CGRRF1, SMARCC2, SORBS1, and XPA were 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 were SCGB3A1 (54%), RASSF1A (29%), and HOXA9 (26%). CDH13 and HOXB5 were methylated at low frequencies (10-15%), and EMX2, MSX1, RUNX3, SORBS1, and XPA only rarely (<10%). In conclusion, this study has identified several novel epigenetically deregulated target genes in TGCT development, including homeobox genes and SCGB3A1, suggesting that epigenetic inactivation of key genes in normal development also has an important role in TGCTs.
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Centre, Oslo, Norway.
authors.forename: G E
authors.initials: GE
authors.lastname: Lind
authors.forename: R I
authors.initials: RI
authors.lastname: Skotheim
authors.forename: M F
authors.initials: MF
authors.lastname: Fraga
authors.forename: V M
authors.initials: VM
authors.lastname: Abeler
authors.forename: M
authors.initials: M
authors.lastname: Esteller
authors.forename: R A
authors.initials: RA
authors.lastname: Lothe
mesh_terms: D018236:Carcinoma, Embryonal / Q000235:genetics; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D018240:Endodermal Sinus Tumor / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005801:Genes, Homeobox / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008745:Methylation; D009363:Neoplasm Proteins / Q000235:genetics; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D016133:Polymerase Chain Reaction / Q000379:methods; D018239:Seminoma / Q000235:genetics; D013724:Teratoma / Q000235:genetics; D013736:Testicular Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D016207:Cytokines; D004273:DNA, Neoplasm; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; C434732:SCGB3A1 protein, human; D025521:Tumor Suppressor Proteins; C097899:homeobox protein HOXA9