Germline and somatic mutations in patients with multiple primary melanomas: A next generation sequencing study

Milena Casula, Panagiotis Paliogiannis, Fabrizio Ayala, Vincenzo De Giorgi, Ignazio Stanganelli, Mario Mandalà, Maria Colombino, Antonella Manca, Maria Cristina Sini, Corrado Caracò, Paolo Antonio Ascierto, Rosanna Rita Satta, Maria Filomena Dedola, Salvatore Denti, Maria Antonietta Fedeli, Maria Antonietta Montesu, Stefano Profili, Tiziana Scotto, Germana Sini, Francesco TandaAmelia Lissia, Antonio Cossu, Giuseppe Palmieri, Paola Ghiorzo, Paola Queirolo, Pietro Quaglino, Gerardo Botti, Vanna Chiarion Sileni, Anna Maria Di Giacomo

Research output: Contribution to journalArticlepeer-review


Introduction: Multiple primary melanomas (MPM) occur up to 8% of patients with cutaneous malignant melanoma (CMM). They are often sporadic harbouring several somatic mutations, but also familial cases harbouring a CDKN2A germline mutation have been describe in Caucasian populations. The aim of this study was to investigate the incidence, the distribution patterns and the impact of known and unknown germline and somatic mutations in patients with MPM from Italy. Materials and methods: One-hundred and two MPM patients were enrolled for germline mutation analysis, and five patients with at least four MPMs were identified for somatic mutation analysis. The demographic, pathologic and clinical features were retrieved from medical records. Molecular analysis for both germline and somatic mutations was performed in genomic DNA from peripheral blood and tissue samples, respectively, through a next generation sequencing approach, using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup for somatic analysis and a commercial cancer hotspot panel for somatic analysis. Results: CDKN2A mutations were detected in 6/16 (37.5%) and 3/86 (3.5%) MPM cases with and without family history for melanoma, respectively. Furthermore, multiple MC1R and, to a lesser extent, ATM variants have been identified. BAP1 variants were found only in MPM patients from southern Italy. The most frequent somatic variants were the pathogenic BRAF V600E and TP53, followed by KIT, PIK3CA, KDR, and NRAS. Single APC, ERBB4, MET, JAK3 and other variants with unknown function were also detected. Conclusions: CDNK2A mutation is the most relevant susceptibility mutation in Italian patients with MPM, especially those with a family history for CMM. The prevalence of this mutation and other sequence variants identified in this study varies among specific sub-populations. Furthermore, some heterogeneity in driver somatic mutations between sporadic MPMs has been observed, as well as in a number of associated sequence variants the clinical impact of which needs to be further elucidated.

Original languageEnglish
Article number772
JournalBMC Cancer
Issue number1
Publication statusPublished - Aug 5 2019


  • BRAF
  • Cancer
  • CDKN2A
  • Melanoma
  • Mutations
  • NGS
  • Skin

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research


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