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Journal of the American Academy of Dermatology
Volume 74, n° 2
pages 325-332 (février 2016)
Doi : 10.1016/j.jaad.2015.09.053
accepted : 29 September 2015
Original Articles

Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup
 

William Bruno, MD, PhD a, c, Lorenza Pastorino, PhD a, c, , Paola Ghiorzo, PhD a, c, Virginia Andreotti, PhD a, Claudia Martinuzzi, MSc a, b, Chiara Menin, PhD g, Lisa Elefanti, PhD g, Camilla Stagni, PhD i, Antonella Vecchiato, MD h, Monica Rodolfo, PhD j, Andrea Maurichi, MD k, Siranoush Manoukian, MD, PhD l, Vincenzo De Giorgi, MD m, Imma Savarese, MD m, Francesca Gensini, MD, PhD n, Lorenzo Borgognoni, MD o, Alessandro Testori, MD p, Giuseppe Spadola, MD p, Mario Mandalà, MD q, Gianlorenzo Imberti, MD r, Paola Savoia, MD s, Chiara Astrua, MD s, Anna Maria Ronco, MD t, Alessandra Farnetti, MD t, Maria Grazia Tibiletti, PhD u, Maurizio Lombardo, MD v, Giuseppe Palmieri, PhD w, Fabrizio Ayala, MD x, Paolo Ascierto, MD x, Giovanni Ghigliotti, MD d, Marisa Muggianu, MD e, Francesco Spagnolo, MD e, Virginia Picasso, MD f, Enrica Teresa Tanda, MD f, Paola Queirolo, MD f, Giovanna Bianchi-Scarrà, PhD a, c
a Department of Internal Medicine, Medical Specialties and Surgical Science and Integrated Diagnostics, University of Genoa, Genoa, Italy 
b Department of Internal Medicine, Medical Specialties and Surgical Science and Integrated Diagnostics, University of Genoa, Genoa, Italy 
c Genetics of Rare Cancers, IRCCS AOU San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 
d Dermatology Unit, IRCCS AOU San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 
e Department of Plastic and Reconstructive Surgery, IRCCS AOU San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 
f Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera Universitaria (AOU) San Martino–Istituto Nazionale dei Tumori (IST) Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 
g Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, Istituto Oncologico Veneto (IOV)-IRCCS, Padua, Italy 
h Melanoma and Soft Tissue Sarcoma Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy 
i Section of Oncology and Immunology, Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy 
j Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy 
k Melanoma and Sarcoma Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy 
l Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy 
m Department of Dermatology, University of Florence, Florence, Italy 
n Unit of Medical Genetics, Department of Biomedical Experimental and Clinical Sciences, University of Florence, Florence, Italy 
o Plastic Surgery Unit, Regional Melanoma Referral Center, Santa Maria Annunziata Hospital, Florence, Italy 
p Division of Dermatoncological Surgery, European Institute of Oncology, Milan, Italy 
q Medical Oncology Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy 
r Dermatology Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy 
s Department of Medical Sciences, Dermatology Section, University of Turin, Turin, Italy 
t Dermatoncological Surgery Unit, Presidio Sanitario Gradenigo, Turin, Italy 
u Anatomopathology Unit, Università dell'Insubria, Ospedale di Circolo, Varese, Italy 
v Dermatology Unit, Ospedale di Circolo, Varese, Italy 
w Cancer Genetics Unit, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy 
x Department of Melanoma, National Cancer Institute Pascale Foundation, Naples, Italy 

Reprint requests: Lorenza Pastorino, PhD, Departments of Internal Medicine and Medical Specialties, University of Genoa, Genetics of Rare Cancers, IRCCS AOU San Martino-IST, V.le Benedetto XV 6, 16132, Genoa, Italy.
Abstract
Background

Multiple primary melanoma (MPM), in concert with a positive family history, is a predictor of cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A ) germline mutations. A rule regarding the presence of either 2 or 3 or more cancer events (melanoma and pancreatic cancer) in low or high melanoma incidence populations, respectively, has been established to select patients for genetic referral.

Objective

We sought to determine the CDKN2A /CDK4 /microphthalmia-associated transcription factor mutation rate among Italian patients with MPM to appropriately direct genetic counseling regardless of family history.

Methods

In all, 587 patients with MPM and an equal number with single primary melanomas and control subjects were consecutively enrolled at the participating centers and tested for CDKN2A , CDK4 , and microphthalmia-associated transcription factor.

Results

CDKN2A germline mutations were found in 19% of patients with MPM versus 4.4% of patients with single primary melanoma. In familial MPM cases the mutation rate varied from 36.6% to 58.8%, whereas in sporadic MPM cases it varied from 8.2% to 17.6% in patients with 2 and 3 or more melanomas, respectively. The microphthalmia-associated transcription factor E318K mutation accounted for 3% of MPM cases altogether.

Limitations

The study was hospital based, not population based. Rare novel susceptibility genes were not tested.

Conclusion

Italian patients who developed 2 melanomas, even in situ, should be referred for genetic counseling even in the absence of family history.

The full text of this article is available in PDF format.

Key words : cyclin-dependent kinase, cyclin-dependent kinase inhibitor 2A, family history, genetic assessment, melanoma, microphthalmia-associated transcription factor, mutation, pancreatic cancer

Abbreviations used : CDK, CDKN2A, MITF, MPM, SIGU, SPM



 Drs Queirolo and Bianchi-Scarrà contributed equally to this study.
 Partially funded by Associazione Italiana per la Ricerca sul Cancro (AIRC) 15460 to Dr Ghiorzo, University of Genoa Progetto Ricerca Ateneo (PRA) 2013-2014 to Dr Ghiorzo, Italian Ministry of Health funds to Drs Bianchi-Scarrà and Ghiorzo, Italian Melanoma Intergroup fellowship to Dr Andreotti, Italian Melanoma Intergroup and Emme Rouge Onlus funds in memory of Mara Nahum to Drs Bruno and Rodolfo, and Sardinia Regional Government (Regione Autonoma della Sardegna) funds to Dr Palmieri.
 Conflicts of interest: None declared.



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