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Microphthalmia-Associated Transcription Factor Gene Amplification in Metastatic Melanoma Is a Prognostic Marker for Patient Survival, But Not a Predictive Marker for Chemosensitivity and Chemotherapy Response

Authors' Affiliations: ¹ Skin Cancer Unit, German Cancer Research Center and University Medical Center Mannheim, Mannheim, Germany; ² Department of Dermatology, Julius-Maximilian University, Würzburg, Germany; and ³ Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Jürgen Becker, Department of Dermatology, Julius-Maximilians University, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany. Phone: 49-931-201-26396; Fax: 49-931-201-26700; E-mail: becker_jc{at}klinik.uni-wuerzburg.de.

Purpose: The microphthalmia-associated transcription factor (MITF) is regarded as a key oncogene of the melanocytic lineage since it was detected by a genome-wide analysis to be strongly amplified in 15% to 20% of metastatic melanomas. MITF gene amplification was shown to be associated with a reduced survival in metastatic melanoma patients, and reduction of MITF activity was shown to sensitize melanoma cell lines to chemotherapeutics, suggesting the intratumoral MITF gene copy number as a predictive biomarker of response and survival after chemotherapy.

Patients and Methods: To validate this hypothesis, we investigated MITF gene amplification in tumor tissues obtained from 116 metastatic melanoma patients before an individualized sensitivity-directed chemotherapy using quantitative real-time PCR. MITF amplification rates were correlated with tumor chemosensitivity quantified by an ATP-based luminescence assay and with chemotherapy outcome in terms of response and survival.

Results: Of 116 tumor tissues, 104 were evaluable for MITF gene amplification. Strong amplification (4 copies per cell) was detected in 24 of 104 tissues (23%), whereas 62 of 104 tissues (60%) harbored >3 copies per cell. Strong MITF gene amplification was associated with a reduced disease-specific survival (P = 0.031). However, no correlation was found between MITF copy number and in vitro chemosensitivity or in vivo chemotherapy response.

Conclusion: Our findings suggest that strong amplifications of the melanoma oncogene MITF affects patient survival but does not influence tumor chemosensitivity and chemotherapy response. Thus, the MITF gene copy number seems a useful prognostic marker in metastatic melanoma but could not be confirmed as a predictive marker of chemosensitivity and chemotherapy response.