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Ataxia Telangiectasia-Mutated Gene Is a Possible Biomarker for Discrimination of Infiltrative Deep Penetrating Nevi and Metastatic Vertical Growth Phase Melanoma

¹ Department of Dermatology and ² Institute of Human Genetics, Regensburg University Medical Center; ³ Institute of Functional Genomics and ⁴ Center of Excellence for Fluorescent Bioanalysis, University of Regensburg, Regensburg, Germany

Requests for reprints: Alexander Roesch, Department of Dermatology, Regensburg University Medical Center, Franz-Josef Strauss-Allee 11, D-93053 Regensburg, Germany. Phone: 49-941-944-9678. E-mail: alexander.roesch{at}klinik.uni-regensburg.de

The deep penetrating nevus (DPN) is a variant of benign melanocytic nevus with clinical and histologic features mimicking vertical growth phase, nodular malignant melanoma (NMM). Because fatal misdiagnosis such as NMM occurs in 29% to 40% of the DPN, molecular differentiation markers are highly desirable. Beyond the clinical demand for precise diagnosis and diagnosis-adapted, preventive therapeutic strategies, the DPN represents a valuable natural model for melanocytic invasion without metastatic potential that per se deserves further investigations. In the present study, at first, we used a genome-wide, microarray-based approach to systematically prescreen for possible molecular markers differentially expressed between selected cases of typical DPN (n = 4) and metastatic NMM controls (n = 4). Gene expression profiling was done on Affymetrix Human X3P microarrays. Of the 47,000 genes spotted, we identified a list of 227 transcripts, which remained significantly regulated at a false discovery rate of 5%. Subsequently, we verified the expression of a subset of the most interesting transcripts in a larger immunohistochemical series (DPN, n = 17; NMM, n = 16). Of these transcripts, three were selected for immunohistochemical confirmation: tissue inhibitor of metalloproteinase-2, tumor protein D52, and ataxia telangiectasia-mutated gene (ATM). Additional criteria for selection from the list of 227 significantly regulated transcripts were grouping into functional Ingenuity networks and a known melanoma- or cancer-relevant function. Following these criteria, we detected a highly significant up-regulation of ATM transcription in NMM, which was also mirrored by ATM protein up-regulation. In contrast to the other markers, ATM particularly might serve as a suitable diagnostic and reliable discriminator of DPN/NMM because ATM immunoreactivity also showed a reliable staining consistency within all samples of both entities. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2486–90)