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Characteristic promoter hypermethylation signatures in male germ cell tumors

BACKGROUND: Human male germ cell tumors (GCTs) arise from undifferentiated primordial germ cells (PGCs), a stage in which extensive methylation reprogramming occurs. GCTs exhibit pluripotentality and are highly sensitive to cisplatin therapy. The molecular basis of germ cell (GC) transformation, dif...

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Autores principales: Koul, Sanjay, Houldsworth, Jane, Mansukhani, Mahesh M, Donadio, Alessia, McKiernan, James M, Reuter, Victor E, Bosl, George J, Chaganti, Raju S, Murty, Vundavalli V
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC149411/
https://www.ncbi.nlm.nih.gov/pubmed/12495446
http://dx.doi.org/10.1186/1476-4598-1-8
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author Koul, Sanjay
Houldsworth, Jane
Mansukhani, Mahesh M
Donadio, Alessia
McKiernan, James M
Reuter, Victor E
Bosl, George J
Chaganti, Raju S
Murty, Vundavalli V
author_facet Koul, Sanjay
Houldsworth, Jane
Mansukhani, Mahesh M
Donadio, Alessia
McKiernan, James M
Reuter, Victor E
Bosl, George J
Chaganti, Raju S
Murty, Vundavalli V
author_sort Koul, Sanjay
collection PubMed
description BACKGROUND: Human male germ cell tumors (GCTs) arise from undifferentiated primordial germ cells (PGCs), a stage in which extensive methylation reprogramming occurs. GCTs exhibit pluripotentality and are highly sensitive to cisplatin therapy. The molecular basis of germ cell (GC) transformation, differentiation, and exquisite treatment response is poorly understood. RESULTS: To assess the role and mechanism of promoter hypermethylation, we analyzed CpG islands of 21 gene promoters by methylation-specific PCR in seminomatous (SGCT) and nonseminomatous (NSGCT) GCTs. We found 60% of the NSGCTs demonstrating methylation in one or more gene promoters whereas SGCTs showed a near-absence of methylation, therefore identifying distinct methylation patterns in the two major histologies of GCT. DNA repair genes MGMT, RASSF1A, and BRCA1, and a transcriptional repressor gene HIC1, were frequently methylated in the NSGCTs. The promoter hypermethylation was associated with gene silencing in most methylated genes, and reactivation of gene expression occured upon treatment with 5-Aza-2' deoxycytidine in GCT cell lines. CONCLUSIONS: Our results, therefore, suggest a potential role for epigenetic modification of critical tumor suppressor genes in pathways relevant to GC transformation, differentiation, and treatment response.
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spelling pubmed-1494112003-02-25 Characteristic promoter hypermethylation signatures in male germ cell tumors Koul, Sanjay Houldsworth, Jane Mansukhani, Mahesh M Donadio, Alessia McKiernan, James M Reuter, Victor E Bosl, George J Chaganti, Raju S Murty, Vundavalli V Mol Cancer Research BACKGROUND: Human male germ cell tumors (GCTs) arise from undifferentiated primordial germ cells (PGCs), a stage in which extensive methylation reprogramming occurs. GCTs exhibit pluripotentality and are highly sensitive to cisplatin therapy. The molecular basis of germ cell (GC) transformation, differentiation, and exquisite treatment response is poorly understood. RESULTS: To assess the role and mechanism of promoter hypermethylation, we analyzed CpG islands of 21 gene promoters by methylation-specific PCR in seminomatous (SGCT) and nonseminomatous (NSGCT) GCTs. We found 60% of the NSGCTs demonstrating methylation in one or more gene promoters whereas SGCTs showed a near-absence of methylation, therefore identifying distinct methylation patterns in the two major histologies of GCT. DNA repair genes MGMT, RASSF1A, and BRCA1, and a transcriptional repressor gene HIC1, were frequently methylated in the NSGCTs. The promoter hypermethylation was associated with gene silencing in most methylated genes, and reactivation of gene expression occured upon treatment with 5-Aza-2' deoxycytidine in GCT cell lines. CONCLUSIONS: Our results, therefore, suggest a potential role for epigenetic modification of critical tumor suppressor genes in pathways relevant to GC transformation, differentiation, and treatment response. BioMed Central 2002-11-28 /pmc/articles/PMC149411/ /pubmed/12495446 http://dx.doi.org/10.1186/1476-4598-1-8 Text en Copyright © 2002 Koul et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
spellingShingle Research
Koul, Sanjay
Houldsworth, Jane
Mansukhani, Mahesh M
Donadio, Alessia
McKiernan, James M
Reuter, Victor E
Bosl, George J
Chaganti, Raju S
Murty, Vundavalli V
Characteristic promoter hypermethylation signatures in male germ cell tumors
title Characteristic promoter hypermethylation signatures in male germ cell tumors
title_full Characteristic promoter hypermethylation signatures in male germ cell tumors
title_fullStr Characteristic promoter hypermethylation signatures in male germ cell tumors
title_full_unstemmed Characteristic promoter hypermethylation signatures in male germ cell tumors
title_short Characteristic promoter hypermethylation signatures in male germ cell tumors
title_sort characteristic promoter hypermethylation signatures in male germ cell tumors
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC149411/
https://www.ncbi.nlm.nih.gov/pubmed/12495446
http://dx.doi.org/10.1186/1476-4598-1-8
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