Correspondence

Molecular Mechanisms in Melanoma

N Engl J Med 2006; 355:1395-1396September 28, 2006

Article

To the Editor:

The review of melanoma by Miller and Mihm (July 6 issue)1 clearly characterizes the linear progression of melanocytic lesions, from the morphologic perspective to the molecular perspective.2,3 However, the genetic alterations would have more relevance if they result in kinetic advantage and progression. My colleagues and I have studied a series of dysplastic nevi (92 low-grade and 31 high-grade lesions) and melanomas in situ (15 lesions) using proliferation (Ki-67 labeling), apoptosis (in situ end labeling), and cell-cycle regulators (RB1, TP53, p21WAF1, and p27Kip1).4 Our analysis highlighted a clear topographic heterogeneity at the early stage of melanocytic transformation: slow kinetics in the dermal compartment of low-grade melanocytic dysplasia and a higher incidence of TP53 alterations in high-grade melanocytic dysplasia than in low-grade dysplasia and melanomas. These findings suggest that melanocytic dysplasia is a marker of the risk of melanoma rather than a direct precursor.

Salvador J. Diaz-Cano, M.D., Ph.D.
King's College Hospital, London SE5 9RS, United Kingdom
salvador.diaz-cano@kcl.ac.uk

4 References

1. 1

   Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med 2006;355:51-65
   Full Text | Web of Science | Medline

2. 2

   Meltzer PS. Genetic diversity in melanoma. N Engl J Med 2005;353:2104-2107
   Full Text | Web of Science | Medline

3. 3

   Bittner M, Meltzer P, Chen Y, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature 2000;406:536-540
   CrossRef | Web of Science | Medline

4. 4

   Pozo L, Naase M, Cerio R, Blanes A, Diaz-Cano SJ. Critical analysis of histologic criteria for grading atypical (dysplastic) melanocytic nevi. Am J Clin Pathol 2001;115:194-204
   CrossRef | Web of Science | Medline

To the Editor:

Miller and Mihm suggest that the gene encoding the microphthalmia-associated transcription factor (MITF) is a key oncogene of the melanocytic lineage, since it was strongly amplified in 15 to 20% of metastatic melanomas.1,2 Furthermore, amplification of the MITF gene and overexpression of the MITF protein were associated with decreased overall survival among patients with metastatic melanoma. MITF overexpression was also associated with impaired sensitivity to cytotoxic agents in melanoma cell lines, suggesting that the number of copies of the MITF gene is a surrogate biomarker of the response to chemotherapy.2 To validate these findings, we investigated MITF gene amplification in tumor tissues from 90 patients with metastatic melanoma before the administration of individualized, sensitivity-directed chemotherapy.3 Strong amplification of the MITF gene (more than four copies per cell) was found in only 4 of 90 tumors (4.4%), whereas 15 of 90 tumors (16.7%) had intermediate amplification (more than two copies per cell). We found no association between the number of copies of the MITF gene and chemosensitivity, the outcome of chemotherapy, or overall survival. Hence, our findings suggest that the MITF gene has a smaller influence on melanoma than has been assumed previously.

Selma Ugurel, M.D.
German Cancer Research Center, 68167 Mannheim, Germany
s.ugurel@dkfz.de

Roland Houben, Ph.D.
Jürgen C. Becker, M.D., Ph.D.
Julius-Maximilians University, 97080 Würzburg, Germany

3 References

1. 1

   McGill GG, Horstmann M, Widlund HR, et al. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 2002;109:707-718
   CrossRef | Web of Science | Medline

2. 2

   Garraway LA, Widlund HR, Rubin MA, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 2005;436:117-122
   CrossRef | Web of Science | Medline

3. 3

   Ugurel S, Schadendorf D, Pföhler C, et al. In vitro drug sensitivity predicts response and survival after individualized sensitivity-directed chemotherapy in metastatic melanoma — a multicenter phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG). Clin Cancer Res (in press).
   

To the Editor:

Miller and Mihm did not mention the role of epigenetic disturbances in melanoma. A number of genes are affected by alterations in DNA-methylation patterns in melanoma cells.1 Aggressive vertical growth can lead to metastasis, and it has been suggested that aberrant methylation of CpG islands may take place during this phase.1 This finding may have clinical application, since epigenetic inactivation or the action of tumor suppressors can be reversed by demethylating agents plus histone deacetylase inhibitors.2

Salvador Vale, M.D.
Laboratorio Trinidad, 01460 Distrito Federal, Mexico
svalemayorga@yahoo.com.mx

2 References

1. 1

   Gallagher WM, Bergin OE, Rafferty M, et al. Multiple markers for melanoma progression regulated by DNA methylation: insights from transcriptomic studies. Carcinogenesis 2005;26:1856-1867
   CrossRef | Web of Science | Medline

2. 2

   Glasspool RM, Teodoridis JM, Brown R. Epigenetics as a mechanism driving polygenic clinical drug resistance. Br J Cancer 2006;94:1087-1092
   CrossRef | Web of Science | Medline

Author/Editor Response

The evidence in cell culture that MITF functions as an oncogene in conjunction with BRAF 1 provides a basis for the advantage that at least some melanomas gain by the overexpression of MITF. However, the previous observation that MITF is present in nearly all melanomas,2 despite its function in differentiation, indicates the need for melanomas to maintain the expression of MITF.

This phenomenon of dependence of a tumor on lineage-specific genes3 suggests that further knowledge of the role of MITF in the survival and development of normal melanoctyes is essential for understanding the “addiction” of melanoma to the MITF-driven genetic program.

Arlo Miller, M.D., Ph.D.
Martin C. Mihm, Jr., M.D.
Massachusetts General Hospital, Boston, MA 02114

3 References

1. 1

   Garraway LA, Widlund HR, Rubin MA, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 2005;436:117-122
   CrossRef | Web of Science | Medline

2. 2

   Granter SR, Weilbaecher KN, Quigley C, Fisher DE. Role for microphthalmia transcription factor in the diagnosis of metastatic malignant melanoma. Appl Immunohistochem Mol Morphol 2002;10:47-51
   CrossRef | Medline

3. 3

   Garraway LA, Sellers WR. Lineage dependency and lineage-survival oncogenes in human cancer. Nat Rev Cancer 2006;6:593-602
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Ehab A Husain, Charles Mein, Lucia Pozo, Alfredo Blanes, Salvador J Diaz-Cano. (2011) Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi. Modern Pathology 24:4, 471-486
   CrossRef

2. 2

   Federica Felicetti, M Cristina Errico, Patrizia Segnalini, Gianfranco Mattia, Alessandra Carè. (2008) MicroRNA-221 and -222 pathway controls melanoma progression. Expert Review of Anticancer Therapy 8:11, 1759-1765
   CrossRef