title: Ataxia telangiectasia-mutated gene is a possible biomarker for discrimination of infiltrative deep penetrating nevi and metastatic vertical growth phase melanoma.
abstract: 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.
authors.affiliation: Department of Dermatology, Regensburg University Medical Center, Franz-Josef Strauss-Allee 11, D-93053 Regensburg, Germany. alexander.roesch@klinik.uni-regensburg.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Roesch
authors.forename: Bernd
authors.initials: B
authors.lastname: Becker
authors.forename: Stefan
authors.initials: S
authors.lastname: Bentink
authors.forename: Rainer
authors.initials: R
authors.lastname: Spang
authors.forename: Annegret
authors.initials: A
authors.lastname: Vogl
authors.forename: Ilja
authors.initials: I
authors.lastname: Hagen
authors.forename: Michael
authors.initials: M
authors.lastname: Landthaler
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogt
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D014408:Biomarkers, Tumor / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003937:Diagnosis, Differential; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D009508:Nevus, Pigmented / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases