Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma.
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.
Voelter
Verena
V
Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland. vvoelter@celgene.com
Diserens
Annie-Claire
AC
Moulin
Alexandre
A
Nagel
Georg
G
Yan
Pu
P
Migliavacca
Eugenia
E
Rimoldi
Donata
D
Hamou
Marie-France
MF
Kaina
Bernd
B
Leyvraz
Serge
S
Hegi
Monika E
ME
D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary*; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D040081:Protein Array Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014604:Uveal Neoplasms / Q000473:pathology*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes