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

• Published in: Clinical cancer research Vol. 13; no. 21; pp. 6344 - 6350
• Main Authors: UGUREL, Selma, HOUBEN, Roland, SCHRAMA, David, VOIGT, Heike, ZAPATKA, Marc, SCHADENDORF, Dirk, BRBCKER, Eva B, BECKER, Jürgen C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-11-2007
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biomarkers, Tumor; chemosensitivity; Dermatology; Female; Gene Amplification; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Medical sciences; melanoma; Melanoma - metabolism; Melanoma - pathology; Microphthalmia-Associated Transcription Factor - biosynthesis; Microphthalmia-Associated Transcription Factor - genetics; Middle Aged; MITF; Pharmacology. Drug treatments; Prognosis; survival; Treatment Outcome; Tumors of the skin and soft tissue. Premalignant lesions; Human; Prognosis; Transcription factor MITF; Biological marker; Malignant tumor; Metastasis; Survival; Gene amplification; Chemotherapy; Treatment; Malignant melanoma; Chemosensitivity; Advanced stage; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-2682

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.