Archives of Dermatological Research

, Volume 310, Issue 10, pp 769–784 | Cite as

Melanoma-prone families: new evidence of distinctive clinical and histological features of melanomas in CDKN2A mutation carriers

  • Laura Cristina GironiEmail author
  • Enrico Colombo
  • Barbara Pasini
  • Roberto Giorgione
  • Pamela Farinelli
  • Francesca Zottarelli
  • Elia Esposto
  • Elisa Zavattaro
  • Elias Allara
  • Paola Ogliara
  • Marta Betti
  • Irma Dianzani
  • Paola Savoia
Original Paper


Germline mutations on the CDKN2A gene, the most important known genetic factors associated with cutaneous melanomas (CMs), predispose carriers to multiple primary CMs (MPMs) with higher frequency and younger onset compared to non-carriers. Most of the largest published studies concerning clinical and histological characteristics of CMs with CDKN2A mutation carriers did not specify if the described CMs are first or subsequent to the first, and they used sporadic CMs from non-genotyped patients as controls. We conducted a single-centre observational study to compare clinical and histological CM features of 32 unrelated carriers (MUT) of 5 germline CDKN2A mutations (one of which was never previously described) compared to 100 genotyped wild-type (WT) patients. We stratified the data based on time of diagnosis, anatomical site and histological subtype of CMs, demonstrating several significant unreported differences between the two groups. MUT developed a higher number of dysplastic nevi and MPMs. We proved for the first time that anatomical distribution of CMs in MUT was independent of gender, unlike WTs. MUTs developed in situ and superficial spreading melanomas (SSMs) more frequently, with significantly higher number of SSMs on the head/neck. In MUTs, Breslow thickness was significantly lower for all invasive CMs. When CMs were stratified on the basis of the time of occurrence, statistical significance was maintained only for SSMs subsequent to the first. In WTs, Clark level was significantly higher, and ulceration was more prevalent than in MUTs. Significant differences in ulceration were observed only in SSMs. In nodular CMs, we did not find differences in terms of Breslow thickness or ulceration between WTs and MUTs. In situ CMs developed 10 years earlier in MUTs with respect to WTs, whereas no significant differences were observed in invasive CMs. In contrast to those reported previously by other authors, we did not find a difference in skin phototype.


CDKN2A Familial melanoma Cutaneous melanoma Melanoma-susceptibility genes Risk factor for cutaneous melanoma 



Cutaneous melanoma


Pancreatic cancer


Carrier of CDKN2A germline mutation


Wild type


Uveal melanoma


Familial cancer syndrome


First CM


CM diagnosed within 3 months after the first (metachronous CM)


Multiple primary melanomas


Sentinel node biopsy




Sentinel node metastases.




Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval(Research involving Human Participants)

This study obtained approval from the Ethics Committee of our Institution (Comitato Etico Interaziendale, Azienda Ospedaliero Universitaria Maggiore della Carità di Novara, Italy).

Informed consent

Written informed consent for genetic analysis was obtained from all patients.

Supplementary material

403_2018_1866_MOESM1_ESM.doc (22 kb)
Supplementary material 1 (DOC 22 KB)


  1. 1.
    Abdel-Rahman MH, Pilarski R, Cebulla CM et al (2011) Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet 48(12):856–859CrossRefGoogle Scholar
  2. 2.
    Aguilera P, Malvehy J, Carrera C et al (2014) Clinical and histopathological characteristics between familial and sporadic melanoma in Barcelona, Spain. J Clin Exp Dermatol Res 5(5):231PubMedPubMedCentralGoogle Scholar
  3. 3.
    AIRTUM Working Group (2016) The contribution of the Italian association of cancer registries (AIRTUM). Epidemiol Prev 40(5Suppl2):28–30Google Scholar
  4. 4.
    Balch CM, Gershenwald JE, Soong SJ et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27(36):6199–6206CrossRefGoogle Scholar
  5. 5.
    Battaglia A (2014) The importance of multidisciplinary approach in early detection of BAP1 tumor predisposition syndrome: clinical management and risk assessment. Clin Med Insights Oncol 8:37–47CrossRefGoogle Scholar
  6. 6.
    Beddingfield FC (2003) The melanoma epidemic: res ipsa loquitor. Oncologist 8(5):459–465CrossRefGoogle Scholar
  7. 7.
    Bertolotto C (2013) Melanoma: from melanocyte to genetic alterations and clinical options. Scientifica (Cairo) 2013:635203Google Scholar
  8. 8.
    Bertolotto C, Lesueur F, Giuliano S et al (2011) A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480(7375):94–98CrossRefGoogle Scholar
  9. 9.
    Betaille V, de Vries E (2008) Melanoma–Part 1: epidemiology, risk factors, and prevention. BMJ 337:a2249CrossRefGoogle Scholar
  10. 10.
    Betti M, Aspesi A, Biasi A et al (2016) CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma. Cancer Lett 378(2):120–130CrossRefGoogle Scholar
  11. 11.
    Bray F, Ren JS, Masuyer E, Ferlay J (2013) Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer 132(5):1133–1145CrossRefGoogle Scholar
  12. 12.
    Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G (2013) BAP1 and cancer. Nat Rev Cancer 13:153–159CrossRefGoogle Scholar
  13. 13.
    Chaudru V, Laud K, Avril MF et al (2005) Melanocortin-1 receptor (MC1R) gene variants and dysplastic nevi modify penetrance of CDKN2A mutations in French melanoma-prone pedigrees. Cancer Epidemiol Biomarkers Prev 14(10):2384–2390CrossRefGoogle Scholar
  14. 14.
    Dummer R, Hauschild A, Guggenheim M et al (2012) Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(Suppl 7):vii86–91CrossRefGoogle Scholar
  15. 15.
    Fava P, Astrua C, Chiarugi A et al (2015) Differences in clinicopathological features and distribution of risk factors in Italian melanoma patients. Dermatology 230(3):256–262CrossRefGoogle Scholar
  16. 16.
    Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J et al (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49(6):1374–1403CrossRefGoogle Scholar
  17. 17.
    Ferrone CR, Ben Porat L, Panageas KS et al (2005) Clinicopathological features of and risk factors for multiple primary melanomas. JAMA 294(13):1647–1654CrossRefGoogle Scholar
  18. 18.
    Garbe C, Peris K, Hauschild A et al (2012) Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline, Update 2012. Eur J Cancer 48(15):2375–2390CrossRefGoogle Scholar
  19. 19.
    Ghiorzo P, Pastorino L, Queirolo P et al (2013) Prevalence of the E318K MITF germline mutation in Italian melanoma patients: associations with histological subtypes and family cancer history. Pigment Cell Melanoma Res 26(2):259–262CrossRefGoogle Scholar
  20. 20.
    Goldstein AM, Tucker MA (2013) Dysplastic nevi and melanoma. Cancer Epidemiol Biomarkers Prev 22(4):528–532CrossRefGoogle Scholar
  21. 21.
    Helgadottir H, Höiom V, Jönsson G et al (2014) High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families. J Med Genet 51(8):545–552CrossRefGoogle Scholar
  22. 22.
    Horn S, Figl A, Rachakonda PS et al (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339:959–961CrossRefGoogle Scholar
  23. 23.
    Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–959CrossRefGoogle Scholar
  24. 24.
    Leachman SA, Lucero OM, Sampson JE et al (2017) Identification, genetic testing, and management of hereditary melanoma. Cancer Metastasis Rev 36(1):77–90CrossRefGoogle Scholar
  25. 25.
    Måsbäck A, Olsson H, Westerdahl J et al (2002) Clinical and histopathological features of malignant melanoma in germline CDKN2A mutation families. Melanoma Res 12(6):549–557CrossRefGoogle Scholar
  26. 26.
    Miller PJ, Duraisamy S, Newell JA et al (2011) Classifying variants of CDKN2A using computational and laboratory studies. Hum Mutat 32(8):900–911CrossRefGoogle Scholar
  27. 27.
    Pastorino L, Bonelli L, Ghiorzo P et al (2008) CDKN2A mutations and MC1R variants in Italian patients with single or multiple primary melanoma. Pigment Cell Melanoma Res 21(6):700–709CrossRefGoogle Scholar
  28. 28.
    Pellegrini C, Maturo MG, Martorelli C et al (2017) Characterization of melanoma susceptibility genes in high-risk patients from Central Italy. Melanoma Res 27(3):258–267CrossRefGoogle Scholar
  29. 29.
    Queirolo P, Acquati M, Kirkwood JM et al (2005) Update: current management issues in malignant melanoma. Melanoma Res 15(5):319–324CrossRefGoogle Scholar
  30. 30.
    Robles-Espinoza CD, Harland M, Ramsay AJ et al (2014) POT1 loss-of-function variants predispose to familial melanoma. Nat Genet 46:478–481CrossRefGoogle Scholar
  31. 31.
    Sargen MR, Kanetsky PA, Newton-Bishop J et al (2015) Histologic features of melanoma associated with CDKN2A genotype. J Am Acad Dermatol 72(3):496–507.e7CrossRefGoogle Scholar
  32. 32.
    Savoia P, Osella-Abate S, Deboli T et al (2012) Clinical and prognostic reports from 270 patients with multiple primary melanomas: a 34-year single-institution study. J Eur Acad Dermatol Venereol 26(7):882–888CrossRefGoogle Scholar
  33. 33.
    Shi J, Yang XR, Ballew B et al (2014) Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet 46:482–486CrossRefGoogle Scholar
  34. 34.
    Soura E, Eliades PJ, Shannon K, Stratigos AJ, Tsao H (2016) Hereditary melanoma: update on syndromes and management: genetics of familial atypical multiple mole melanoma syndrome. J Am Acad Dermatol 74(3):395–407; quiz 408 – 10CrossRefGoogle Scholar
  35. 35.
    Soura E, Eliades PJ, Shannon K, Stratigos AJ, Tsao H (2016) Hereditary melanoma: Update on syndromes and management: emerging melanoma cancer complexes and genetic counseling. J Am Acad Dermatol 74(3):411–420; quiz 421-2CrossRefGoogle Scholar
  36. 36.
    Taylor NJ, Handorf EA, Mitra N et al (2016) Phenotypic and histopathological tumor characteristics according to CDKN2A mutation status among affected members of melanoma families. J Invest Dermatol 136(5):1066–1069CrossRefGoogle Scholar
  37. 37.
    Tsao H, Zhang X, Kwitkiwski K, Finkelstein DM, Sober AJ, Haluska FG (2000) Low prevalence of germline CDKN2A and CDK4 mutations in patients with early-onset melanoma. Arch Dermatol 136:1118–1122CrossRefGoogle Scholar
  38. 38.
    Tucker MA (2009) Melanoma epidemiology. Hematol Oncol Clin North Am 23(3):383–395, viiCrossRefGoogle Scholar
  39. 39.
    Van der Rhee JI, Krijnen P, Gruis NA et al (2011) Clinical and histologic characteristics of malignant melanoma in families with a germline mutation in CDKN2A. J Am Acad Dermatol 65(2):281–288CrossRefGoogle Scholar
  40. 40.
    Wadt KA, Aoude LG, Johansson P et al (2015) A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clin Genet 88(3):267–272CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Laura Cristina Gironi
    • 1
    Email author
  • Enrico Colombo
    • 2
  • Barbara Pasini
    • 3
  • Roberto Giorgione
    • 1
  • Pamela Farinelli
    • 1
  • Francesca Zottarelli
    • 1
  • Elia Esposto
    • 1
  • Elisa Zavattaro
    • 1
  • Elias Allara
    • 4
  • Paola Ogliara
    • 3
  • Marta Betti
    • 1
  • Irma Dianzani
    • 1
  • Paola Savoia
    • 1
  1. 1.Department of Health SciencesA. Avogadro University of Eastern PiedmontNovaraItaly
  2. 2.Department of Translational MedicineA. Avogadro University of Eastern PiedmontNovaraItaly
  3. 3.Department of Medical SciencesUniversity of TurinTurinItaly
  4. 4.NIHR Blood and Transplant Research Unit, Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK

Personalised recommendations