Open Access Research

Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors

Sanjay Koul1, James M McKiernan2, Gopeshwar Narayan1, Jane Houldsworth34, Jennifer Bacik5, Deborah L Dobrzynski4, Adel M Assaad1, Mahesh Mansukhani1, Victor E Reuter6, George J Bosl4, Raju SK Chaganti34 and Vundavalli VVS Murty17*

  • * Corresponding author: Vundavalli VVS Murty vvm2@columbia.edu

  • † Equal contributors

Author Affiliations

1 Department of Pathology, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA

2 Department of Urology, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA

3 The Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA

4 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA

5 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA

6 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA

7 Institute for Cancer Genetics, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA

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Molecular Cancer 2004, 3:16  doi:10.1186/1476-4598-3-16

Published: 18 May 2004

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.