EGFR gene copy number alterations in primary cutaneous malignant melanomas are associated with poor prognosis

Abstract

Copy number alterations of the epidermal growth factor receptor (EGFR) gene have been extensively analyzed in different cancers, but no data are available for primary malignant melanoma. The aim of the present study was to simultaneously investigate the EGFR gene and chromosome 7 copy number alterations in 81 cutaneous malignant melanomas by interphase FISH and correlate the data with clinicopathological parameters of patients. EGFR mRNA levels were detected by Affymetrix GeneChip Human Genome U133 Plus 2.0 expression arrays for 16 lesions. Both increased gene dosage and chromosome 7 alterations were found in 70% of tumors. Extra EGFR copies were detected in an additional 10% of samples. Polysomy 7 was associated with EGFR gene amplification. Significant correlation was found between EGFR alterations and histological subtypes, tumor thickness, ulceration and metastases formation. Amplification was significantly higher in lesions that developed metastases within 2 years after surgical excision of the primary tumor. Gene copy alterations were associated with elevated mRNA expression in 77% of lesions when compared to tumors with disomic EGFR status, the correlation was not directly proportional to gene copy number. Associations between protein expression and mRNA levels were even less prominent. In conclusion, our study indicates that amplification of the EGFR gene and polysomy 7 are frequent alterations in primary melanomas and are associated with bad prognosis. Further studies are required to clarify whether melanoma patients with EGFR alterations can benefit from anti‐EGFR therapy. © 2007 Wiley‐Liss, Inc.

Somatic alterations in the melanoma genome: A high‐resolution array‐based comparative genomic hybridization study

“…Amplification of MITF is a common feature in metastatic melanoma and is itself subject to complex regulation by oncogenic BRAF through ERK and the transcription factor BRN2 (Garraway et al, 2005;Wellbrock et al, 2008). Similarly other oncogenic loci that showed varying degree and frequency of amplification, thereby underscoring relevance in melanoma, included MDM2, NOTCH2, CCNE1, CCND1, and CDK4 (Curtin et al, 2005;Garraway et al, 2005;GlatzKrieger et al, 2006;Jonsson et al, 2007;Rakosy et al, 2007). Amplification of the GAB2 gene, located at a locus close to CCND1, has been previously linked with melanoma at sun-protected sites and overexpression of the gene potentiates migration and invasion of melanoma cells Horst et al, 2009).…”

Tenascin-C Signaling in melanoma

“…In most adult cells, tonic EGFR signaling becomes anti-adhesive to the point of inducing anoikis. Melanoma cells also express low levels of EGFR protein, at steady state, even though they show increased levels of message RNA and even gene copy number (functionality is shown by the cells being dependent on EGFR signaling for proliferation in vitro 28,29 ). All this suggests a high flux through the system secondary to autocrine receptor activation/downregulation.…”

Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas

“…The potential biomarkers that may be detected in malignant tissues and/ or serum samples, either alone or in combination, to establish the risk of disease progression and as prognostic indicator of melanoma patients include different oncogenic products. Among the more promising molecular biomarkers, there are EGFR, activated pAkt phosphorylated form, microphthalmia-associated transcription factor (MITF), serum amyloid, MIC-1 also designated as growth and differentiation factor-15 (GDF-15), VEGF, interleukin-8 (IL-8) and/or twist [18,23,42,[73][74][75][76][77][78][79][84][85][86][87][88] . More specifically, it has been observed that the EGFR expression was enhanced in primary and metastatic melanoma tissues from patients relative to nonmalignant tissues suggesting that the detection of EGFR could be used as a prognostic indicator to predict the risk of disease progression to metastatic disease states and poor outcome of melanoma patients [86;87] .…”