Frequent epigenetic inactivation of the RASSF1A tumour suppressor gene in testicular tumours and distinct methylation profiles of seminoma and nonseminoma testicular germ cell tumours.
Testicular germ cell tumours (TGCTs) are histologically heterogeneous neoplasms with variable malignant potential. Previously, we demonstrated frequent 3p allele loss in TGCTs, and recently we and others have shown that the 3p21.3 RASSF1A tumour suppressor gene (TSG) is frequently inactivated by promoter hypermethylation in a wide range of cancers including lung, breast, kidney and neuroblastoma. In order to investigate the role of epigenetic events in the pathogenesis of TGCTs, we analysed the promoter methylation status of RASSF1A and nine other genes that may be epigenetically inactivated in cancer (p16(INK4A), APC, MGMT, GSTP1, DAPK, CDH1, CDH13, RARbeta and FHIT) in 24 primary TGCTs (28 histologically distinct components). RASSF1A methylation was detected in four of 10 (40%) seminomas and 15 of 18 (83%) nonseminoma TGCT (NSTGCT) components (P=0.0346). None of the other nine candidate genes were methylated in seminomas, but MGMT (44%), APC (29%) and FHIT (29%) were frequently methylated in NSTGCTs. Furthermore, in two mixed germ cell tumours, the NSTGCT component for one demonstrated RASSF1A, APC and CDH13 promoter methylation, but the seminoma component was unmethylated for all genes analysed. In the second mixed germ cell tumour, the NSTGCT component was methylated for RASSF1A and MGMT, while the seminoma component was methylated only for RASSF1A. In all, 61% NSTGCT components but no seminoma samples demonstrated promoter methylation at two or more genes (P=0.0016). These findings are consistent with a multistep model for TGCT pathogenesis in which RASSF1A methylation occurs early in tumorigenesis and additional epigenetic events characterize progression from seminoma to NSTGCTs.
Honorio
Sofia
S
Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, The Medical School, Edgbaston, UK.
Agathanggelou
Angelo
A
Wernert
Nicolas
N
Rothe
Marcus
M
Maher
Eamonn R
ER
Latif
Farida
F
D017766:Acid Anhydride Hydrolases; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D011401:Promoter Regions, Genetic; D018239:Seminoma / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D025601:Adenomatous Polyposis Coli Protein; D015820:Cadherins; D009363:Neoplasm Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase; D025521:Tumor Suppressor Proteins; D000099170:Bis(5'-adenosyl)triphosphatase; C099972:H-cadherin; C411762:RASSF1 protein, human