The extent of whole-genome copy number alterations predicts aggressive features in primary melanomas Greta Gandolfi 1 , Caterina Longo 2 , Elvira Moscarella 2 , Iris Zalaudek 3 , Valentina Sancisi 1 , Margherita Raucci 2 , Gloria Manzotti 1 , Mila Gugnoni 1 , Simonetta Piana 4 , Giuseppe Argenziano 2,5 and Alessia Ciarrocchi 1 1 Laboratory of Translational Research, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy 2 Skin Cancer Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy 3 Department of Dermatology and Venerology, Non-Melanoma Skin Cancer Unit, Medical University of Graz, Graz, Austria 4 Pathology Unit, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy 5 Dermatology Unit, Second University of Naples, Naples, Italy CORRESPONDENCE Alessia Ciarrocchi, and Giuseppe Argenziano, e-mails: Alessia.Ciarrocchi@asmn.re.it and g.argenziano@gmail.com KEYWORDS primary melanoma/aggressiveness/ copy number alterations/whole-genome SNP array/ dermoscopy PUBLICATION DATA Received 8 June 2015, revised and accepted for publication 2 November 2015, revised and accepted for publication 9 November 2015, published online 17 November 2015 doi: 10.1111/pcmr.12436 Summary Recent evidence indicates that melanoma comprises distinct types of tumors and suggests that specific morphological features may help predict its clinical behavior. Using a SNP-array approach, we quantified chromosomal copy number alterations (CNA) across the whole genome in 41 primary melanomas and found a high degree of heterogeneity in their genomic asset. Association analysis correlating the number and relative length of CNA with clinical, morphological, and dermoscopic attributes of melanoma revealed that features of aggressiveness were strongly linked to the overall amount of genomic damage. Furthermore, we observed that melanoma progression and survival were mainly affected by a low number of large chromosome losses and a high number of small gains.We identified the alterations most frequently associated with aggressive melanoma, and by integrating our data with publicly available gene expression profiles, we identified five genes which expression was found to be necessary for melanoma cells proliferation. In conclusion, this work provides new evidence that the phenotypic heterogeneity of melanoma reflects a parallel genetic diversity and lays the basis to define novel strategies for a more precise prognostic stratification of patients. Introduction Cutaneous melanoma is the most aggressive form of skin cancer (Curtin et al., 2005) and encompasses a heterogeneous family of tumors that differ in terms of clinical aspects and biologic behavior, ranging from indolent tumors with a slow growth rate, very low aggressive potential and good prognosis, to highly aggressive tumors with a fast growth rate, high metastatic potential and possible fatal outcome Significance Primary melanoma is a heterogeneous family of tumors that differ in terms of clinical aspects and biologic behavior. The implementation of in vivo non-invasive diagnostic methods, including dermoscopy and reflectance confocal microscopy, contributed to a better definition of the morphological features of melanoma and provided evidence that the clinical behavior of primary melanoma correlates with specific morphological features of the lesions.In this study, using a high-density SNP array, we showed that melanomas displaying dermoscopic features of aggressiveness are genetically different from the less aggressive forms and are characterized by a strikingly higher degree of genomic damage. Our analysis provides new insights into the genetic heterogeneity of primary melanoma and lays the basis for a more precise prognostic stratification of the patients based on non-invasive dermoscopy. ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 163 Pigment Cell Melanoma Res. 29; 163–175 ORIGINAL ARTICLE