The Impact of O6-Methylguanine-DNA Methyltransferase (MGMT) Promoter Methylation on the Outcomes of Patients with Leiomyosarcoma Treated with Dacarbazine.

Abstract

Dacarbazine is an important drug in the therapeutic landscape of leiomyosarcoma (LMS). Alkylating agents are subjected to resistance mechanisms based on anti-apoptotic pathways and repair mechanisms, including the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). In this retrospective study, the methylation status of the MGMT promoter in histological tumor samples from patients with LMS, dacarbazine-based regimens-treated, was measured and correlated with clinical outcomes aimed at optimizing the use of dacarbazine in soft tissue sarcomas. The patients with unmethylated MGMT had better outcomes than those with methylated MGMT. Patients without MGMT methylation had better Progression Free Survival (PFS) when aged ≥62 years compared to those aged <62 years, while PFS of patients with methylated MGMT was less favorable independently of age (p = 0.0054). The patients without a methylated MGMT gene had higher Disease control rate (DCR). These results are not in agreement with the role of the methylated MGMT gene in other tumors, and with this study, we demonstrated the correlation between methylated MGMT and poor prognosis; despite that, sample smallness, heterogeneity of LMS and of treatment history could be selection bias. Predictive markers of response to chemotherapies in sarcomas remain an unmet need.

• Authors: Lucia Cannella, Rosa Della Monica, Antonella Lucia Marretta, Domenico Iervolino, Bruno Vincenzi, Anna Rosaria De Chiara, Ottavia Clemente, Michela Buonaiuto, Maria Luisa Barretta, Annabella Di Mauro, Massimiliano Di Marzo, Michele Guida, Giuseppe Badalamenti, Lorenzo Chiariotti, Salvatore Tafuto
• Journal: Cells (Cells) Vol. 12 Issue 12 (06 15 2023) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 37371106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Dacarbazine
• DNA
• DNA Modification Methylases
• DNA Repair Enzymes
• Methyltransferases
• MGMT protein, human
• O-(6)-methylguanine
• Temozolomide
• Tumor Suppressor Proteins

Topics

• Humans
• Antineoplastic Agents, Alkylating (pharmacology, therapeutic use)
• Brain Neoplasms (pathology)
• Dacarbazine (therapeutic use)
• DNA
• DNA Methylation (genetics)
• DNA Modification Methylases (genetics, therapeutic use)
• DNA Repair Enzymes (genetics)
• Leiomyosarcoma (drug therapy, genetics)
• Methyltransferases (genetics)
• Retrospective Studies
• Temozolomide (pharmacology, therapeutic use)
• Tumor Suppressor Proteins (genetics)
• Middle Aged