Archivos Españoles de Urología ISSN: 0004-0614 [email protected] Editorial Iniestares S.A. España van der Heijden, Antoine G. THE ROLE OF METHYLATION IN UROLOGICAL TUMOURS Archivos Españoles de Urología, vol. 66, núm. 5, junio, 2013, pp. 432-439 Editorial Iniestares S.A. Madrid, España Available in: http://www.redalyc.org/articulo.oa?id=181031087005 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative PERSPECTIVAS ACTUALES DE LA BIOLOGÍA MOLECULAR APLICADA A LA URO-ONCOLOGÍA Arch. Esp. Urol. 2013; 66 (5): 432-439 THE ROLE OF METHYLATION IN UROLOGICAL TUMOURS Antoine G. van der Heijden Department of Uorology. Radboud University Nijmegen Medical Centre. Nijmegen. The Netherlands. Summary.- Alterations in DNA methylation have been Resumen.- Las alteraciones de la metilación del ADN described in human cancer for more than thirty years se han descrito en el cáncer humano desde hace más now. Since the last decade DNA methylation gets more de 30 años. Desde la última década la metilación del and more important in cancer research. In this review the ADN gana más y más importancia en investigación del different alterations of DNA methylation are discussed in cáncer. En esta revisión se discuten las alteraciones de testicular germ cell tumours, Wilms’ tumours, renal cell la metilación del ADN en los tumores testiculares de carcinomas, urothelial cell carcinomas of the bladder células germinales, tumores de Wilms, carcinomas de and adenocarcinomas of the prostate. Eventually, the células renales, carcinomas de células uroteliales de potential use in diagnostics, prognostics and therapy are vejiga y adenocarcinomas prostáticos. Finalmente se discussed. discute su uso potencial en diagnóstico, pronóstico y tratamiento. Keywords: DNA methylation. Testis. Kidney. Palabras clave: ADN metilación. Riñón. Veji- Bladder. Prostate. Cancer. Wilm’s tumour. Biología ga. Próstata. Cáncer. Tumor de Wilms. Molecular molecular. biology. DNA Methylation Epigenetics is defined as the cellular information, other than the DNA sequence itself, which is heritable during cell division (1). Almost all cancer cells have multiple epigenetic abnormalities, which combine with genetic changes to affect many cellular processes, including cell proliferation and invasion, by silencing tumour-suppressor genes. Epigenetic alterations in cancer cells include DNA methylation, CORRESPONDENCIA histone modification and RNA interference. However, the most studied epigenetic alteration is DNA methylation that can occur at the cytosine that @A.G. van der Heijden MD PhD precedes the guanine in a CpG dinucleotide. While Department of Urology CpG dinucleotides are generally underrepresented in the human genome sequence, the promoter regions Radboud University Nijmegen Medical Centre of around half of the human genes contain CpG- Geert Grooteplein 10 rich areas termed CpG islands that are generally 6525 GA Nijmegen (The Netherlands) unmethylated in normal cells (2). [email protected] Three different types of DNA methylation have been observed in cancer, global hypomethylation, localized hypermethylation and loss of imprinting (3). 433 THE ROLE OF METHYLATION IN UROLOGICAL TUMOURS Hypomethylation represents a decrease of the overall the embryonal carcinoma is undifferentiated and methylcytosine content compared to normal tissue cells may differentiate along an embryonal lineage and is often more pronounced in advanced stages into teratomas, containing tissues from all three germ of malignant disease (4). Methylcytosine levels can layers, or they may differentiate along extra-embryonal be substantially diminished, often to less than 50% lineages into yolk sac tumours or choriocarcinomas of the normal level. To date, there are few reports (11). In general, DNA methylation seems to increase on hypomethylation of human oncogenes associated with differentiation. with activation by overexpression (5). In contrast with hypomethylation, hypermethylation is not a Smiraglia and co-workers demonstrated genome-wide event, but it is found at specific sites significant epigenetic differences between seminomas (6). Hypermethylation has often been observed in the and non-seminomas by restriction landmark genomic promoter regions of many tumour suppressor genes scanning (12). Seminomas showed almost no CpG and is correlated with decreased gene expression. island methylation, in contrast to nonseminomas that Since hypermethylation is concentrated at the promoter show CpG island methylation at a level similar to region it often does not become evident when overall other solid tumours. Furthermore, they demonstrated a DNA methylation is being measured. It has to be higher level of general hypomethylation in seminomas studied on a gene-by-gene basis (7). Hypermethylation compared to nonseminomas. The same year the is considered a key mechanism involved in silencing group of Smith-Sørensen endorsed the significantly of cancer-associated genes and occurs at genes with higher methylation frequency found in nonseminomas diverse functions related to tumorigenesis and tumour compared to seminomas, respectively 67% and 24%; progression and thereby hypermethylation needs to P=0.0003 (13). Furthermore, they discovered a high be considered as an alternative to gene mutation and frequency of MGMT promoter methylation (32/69) deletion. in patients with TGCT. Their conclusion was MGMT contributes to the development of nonseminoma The third alteration related to DNA TGCT. DNA repair genes MGMT and RASSF1A methylation is loss of imprinting (LOI). LOI includes became potential target genes also due to the partial or complete extinction of the difference studies of Koul and Honorio (14,15). Subsequently, between the expression levels of the maternal and several studies on novel hypermethylated target paternal alleles at imprinted loci, which results in an genes have been published (16-18). PRSS21, increased or decreased overall expression. In other SCGB3A1, HIC1, BRCA1, HOXA9, APC, FHIT, words, imprinted genes display a characteristic HOXB5, CDH13 and CDH1 were presented as novel parent-of-origin-specific DNA methylation pattern target genes hypermethylated at high frequencies that results in only a single allele being expressed among nonseminomas. Nevertheless, only a limited (either the paternal or maternal allele) (8). Since number of tumour suppressor genes showed to be the differences in the expression of imprinted alleles inactivated by DNA promoter hypermethylation in are associated with differential methylation, LOI is more than a minor percentage of TGCTs, including associated with alterations in DNA methylation. LOI MGMT, SCGB3A1, RASSF1A, HIC1, and PRSS21. In has been observed most often in tumours with an addition, imprinting defects, DNA hypomethylation, embryonic phenotype (9) and has been implicated in and the presence of the unmethylated XIST gene are the progression of several tumours (10). often observed in TGCTs. In this review the different alterations of DNA Aberrant DNA methylation has the potential methylation in urological tumours are discussed and to improve current TGCT diagnostics. The PRSS21 eventually followed by the potential use in diagnostics, gene can be a useful biomarker. Initially PRSS21 prognostics and therapy. showed to be hypermethylated in 8 out of 8 TGCTs (16). Nevertheless, these findings have not been validated in a larger cohort of patients since. DNA Testicular germ cell tumour methylation might also serve as a prognostic marker for treatment response. Cell line research suggests Testicular germ cell tumour (TGCT) is the most an association between differentiation, global DNA common malignancy among young males and can methylation status and response to chemotherapy be classified into two main histological subgroups: (19). The degree of methylation might explain the seminomas and non-seminomas. Seminomas are chemotherapy sensitivity of TGCT. But what is the generally undifferentiated, and morphologically underlying mechanism for this? Normally primordial they resemble the precursor stage intratubular germ germ cells and embryonic stem cells have an open cell neoplasia. Non-seminomas, on the other hand, chromatin structure that provides a good DNA access. include several histological subtypes. Among these, If TGCT carry a similar chromatic structure, this might 434 A. G. van der Heijden explain the extreme chemotherapy sensitivity; the state markers are being studied to offer patients with low of the chromatin might determine how efficiently DNA risk of relapse a therapy that minimizes the potential targeting drugs can access the DNA. Subsequently, late toxicities, without decreasing the survival rates. increased methylation results in a more condensed Maschietto and co-workers found five genes, TSPAN3, chromatin structure and a decreased chemo sensitivity NCOA6, MPP2, CDO1 and MCM2, which were (20). Koul and co-workers showed a more frequent down regulated in patients with relapse (25). promoter hypermethylation of RASSF1a and HIC1 among chemo resistant tumours (17). These findings Recently, methylation of the RASSF1A did not reach statistical significance due to the limited promoter was found predictive for poor outcome in number of patients but suggest that the promoter Wilms’ tumours (26). Methylation was more frequent