title: Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors.
abstract: BACKGROUND
  Male germ cell tumor (GCT) is a highly curable malignancy, which exhibits exquisite sensitivity to cisplatin treatment. The genetic pathway(s) that determine the chemotherapy sensitivity in GCT remain largely unknown.
  
  
  RESULTS
  We studied epigenetic changes in relation to cisplatin response by examining promoter hypermethylation in a cohort of resistant and sensitive GCTs. Here, we show that promoter hypermethylation of RASSF1A and HIC1 genes is associated with resistance. The promoter hypermethylation and/or the down-regulated expression of MGMT is seen in the majority of tumors. We hypothesize that these epigenetic alterations affecting MGMT play a major role in the exquisite sensitivity to cisplatin, characteristic of GCTs. We also demonstrate that cisplatin treatment induce de novo promoter hypermethylation in vivo. In addition, we show that the acquired cisplatin resistance in vitro alters the expression of specific genes and the highly resistant cells fail to reactivate gene expression after treatment to demethylating and histone deacetylase inhibiting agents.
  
  
  CONCLUSIONS
  Our findings suggest that promoter hypermethylation of RASSF1A and HIC1 genes play a role in resistance of GCT, while the transcriptional inactivation of MGMT by epigenetic alterations confer exquisite sensitivity to cisplatin. These results also implicate defects in epigenetic pathways that regulate gene transcription in cisplatin resistant GCT.
authors.affiliation: Department of Pathology, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA. sk1276@columbia.edu
authors.forename: Sanjay
authors.initials: S
authors.lastname: Koul
authors.forename: James M
authors.initials: JM
authors.lastname: McKiernan
authors.forename: Gopeshwar
authors.initials: G
authors.lastname: Narayan
authors.forename: Jane
authors.initials: J
authors.lastname: Houldsworth
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bacik
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Dobrzynski
authors.forename: Adel M
authors.initials: AM
authors.lastname: Assaad
authors.forename: Mahesh
authors.initials: M
authors.lastname: Mansukhani
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: George J
authors.initials: GJ
authors.lastname: Bosl
authors.forename: Raju S K
authors.initials: RS
authors.lastname: Chaganti
authors.forename: Vundavalli V V S
authors.initials: VV
authors.lastname: Murty
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D019175:DNA Methylation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D052219:Fanconi Anemia Complementation Group F Protein; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D018237:Germinoma / Q000188:drug therapy* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D012189:Retrospective Studies; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology
chemical_list: D004273:DNA, Neoplasm; C499901:FANCF protein, human; D052219:Fanconi Anemia Complementation Group F Protein; C096870:Hic1 protein, mouse; D006657:Histones; D051741:Kruppel-Like Transcription Factors; C411762:RASSF1 protein, human; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002945:Cisplatin