Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations

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BACKGROUND: Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated.

METHODS: CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load.

RESULTS: Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001).

CONCLUSION: Patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.


  • Hildur Helgadottir
  • Paola Ghiorzo
  • Remco van Doorn
  • Susana Puig
  • Max Levin
  • Richard Kefford
  • Martin Lauss
  • Paola Queirolo
  • Lorenza Pastorino
  • Ellen Kapiteijn
  • Miriam Potrony
  • Cristina Carrera
  • Håkan Olsson
  • Veronica Höiom
  • Göran Jönsson
External organisations
  • Leiden University Medical Centre
  • Karolinska Institutet
  • University of Genoa
  • University of Barcelona
  • University of Gothenburg
  • Macquarie University, Sydney
  • Ospedale Policlinico San Martino
  • Skåne University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
  • Dermatology and Venereal Diseases
Original languageEnglish
JournalJournal of Medical Genetics
Publication statusE-pub ahead of print - 2018 Oct 5
Publication categoryResearch