Abstract
BackgroundMale 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Male germ cell tumor (GCT) is a highly curable malignancy, which exhibits exquisite sensitivity to cisplatin treatment
Promoter hypermethylation in relation to chemotherapy resistance and sensitivity Based on our previous observations in GCT, we studied 22 gene promoters for hypermethylation in 70 NSGCTs derived from 60 patients [8]
Other genes that exhibited frequent hypermethylation showed no significant differences (APC, 24% vs. 29%; BRCA1, 31% vs. 30%) between the sensitive and resistant groups. These data, suggest that promoter hypermethylation of RASSF1A and HIC1 is associated with chemotherapy resistance phenotype, while promoter hypermethylation of MGMT and RARB genes is commonly seen in sensitivetumors
Summary
Male germ cell tumor (GCT) is a highly curable malignancy, which exhibits exquisite sensitivity to cisplatin treatment. Adult male germ cell tumors (GCTs) are considered to be a model system for a curable malignancy because of their exquisite sensitivity to cisplatin (CDDP)-based combination (cisplatin, etoposide, with or without bleomycin) chemotherapy. Seminomas are exquisitely sensitive to radiation therapy while NSGCTs are highly sensitive to treatment with CDDP-based chemotherapy. Despite this sensitivity to chemotherapy, 20–30% of metastatic tumors are refractory to initial treatment, requiring salvage therapy and accounting for high mortalitiy. Such patients are treated with high dose and experimental chemotherapy protocols [3]. The underlying molecular basis of this exquisite drug responsiveness of GCT remains to be fully understood [4]
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