Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma.

Abstract

Uveal melanoma is associated with a high mortality rate once metastases occur, with over >90% of metastatic patients dying within less than 1 year from metastases to the liver. The intraarterial hepatic (iah) administration of the alkylating agent fotemustine holds some promise with response rates of 36% and median survival of 15 months. Here, we investigated whether the DNA-repair-protein MGMT may be involved in the variability of response to fotemustine and temozolomide in uveal melanoma. Epigenetic inactivation of MGMT has been demonstrated to be a predictive marker for benefit from alkylating agent therapy in glioblastoma. We found a methylated MGMT promoter in 6% of liver metastases from 34 uveal melanoma patients. The mean MGMT activity measured in liver metastases with negligible liver tissue content was significantly lower than in liver tissue (146 versus 523 fmol/mg protein, p = 0.002). Expression of the MGMT protein was detectable in 50% of 88 metastases by immunohistochemistry on a tissue microarray. Expression was heterogeneous, and in accordance with MGMT activity data, usually lower than in the surrounding liver. Differential MGMT activity/expression between metastasis and liver tissue and more efficient depletion of MGMT with higher doses of alkylating agent therapy using iah delivery may provide the pharmacologic window for the higher response rate. However, these results do not support MGMT methylation status or protein expression as predictive markers for treatment outcome to iah chemotherapy with alkylating agents.

• Authors: Verena Voelter, Annie-Claire Diserens, Alexandre Moulin, Georg Nagel, Pu Yan, Eugenia Migliavacca, Donata Rimoldi, Marie-France Hamou, Bernd Kaina, Serge Leyvraz, Monika E Hegi
• Journal: International journal of cancer (Int J Cancer) Vol. 123 Issue 5 Pg. 1215-8 (Sep 01 2008) ISSN: 1097-0215 [Electronic] United States
• PMID: 18546261 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Tumor Suppressor Proteins
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes

Topics

• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (genetics)
• DNA Methylation
• DNA Modification Methylases (genetics)
• DNA Repair Enzymes (genetics)
• Humans
• Immunohistochemistry
• Liver Neoplasms (drug therapy, genetics, secondary)
• Melanoma (drug therapy, genetics, secondary)
• Predictive Value of Tests
• Promoter Regions, Genetic
• Protein Array Analysis
• Tumor Suppressor Proteins (genetics)
• Uveal Neoplasms (pathology)