Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer.
Methods: These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents.
Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk.
Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.
- ARF, alternate reading frame
- CMM, cutaneous malignant melanoma
- MPM, multiple primary melanoma
- multiple primary melanomas
- pancreatic cancer
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Published Online First 11 August 2006
Funding: This research was supported in part by the intramural research programme of the National Institutes of Health, NCI, DCEG and NHGRI. This work was also partially supported by research grants 1 RO1 CA83115-01A2 “Genetic epidemiology of melanoma” from the National Cancer Institute (DEE); RO1 CA88363 from NCI (NH), National Health and Medical Research Council of Australia (Brisbane group); R01 CA102422 from NCI (LACA), the Tom C Mathews Jr Familial Melanoma Research Clinic, the Huntsman Cancer Foundation (Utah group); Cancer Research UK (Leeds group); grants 01/1546 and 03/0019 from Fondo de Investigaciones Sanitarias, V2003-REDC03/03 and /07, a personal grant to Francisco Cuellar CONACYT, Personal Scholarship 152256/158706, Mexico City, Mexico (Barcelona group); FIRB RBNE0149752001 and COFIN 2004/061840_003 (GB-S; Genoa group); The Swedish Cancer Society: research grants 4860-B05-03XAC, 5012-B05-01PAF, The Swedish Research Council: research grant K2006-74X-20141-01-3 and grants from The Radiumhemmet Research Funds (JH; Stockholm group); Programme Hospitalier de Recherche Clinique Régional d’Ile de France grant AP-HP AOR 01 091 (Marie-Francoise Avril); Research grants and scholarships of the Australian National Health and Medical Research Council (G J M and R F K), The Cancer Councils of Australia, the Australian Cancer Research Foundation, the Melanoma Foundation and Cancer Research Fund of the University of Sydney (Sydney group). P A K was supported by a National Cancer Institute Preventive Oncology Academic Award (K07 CA80700). Some data collection for this publication was assisted by the Utah Cancer Registry supported by NIH Contract NO1-PC-35141, SEER Program, with additional support from the Utah Department of Health and the University of Utah. Partial support for all datasets within the Utah Population Database (UPDB) was provided by the University of Utah Huntsman Cancer Institute.
Competing interests: None.
Authors from Lund Melanoma Study Group:
Lund Cancer Center Department of Oncology, University Hospital, Lund, Sweden (Christian Ingvar, Ake Borg, Johan Westerdahl, Anna Masback, Hakan Olsson)
Additional authors from GenoMEL listed by group/centre:
Barcelona: Dermatology Department (Josep Malvehy) and Genetics Service (Celia Badenas, Remedios Cervera), Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain; Dermatology Department, Hospital Arnau de Vilanova, Universitat de Lleida, Lleida, Spain (Rosa Martí); Genetic Counseling of Cancer, Hospital Sant Joan, Universitat Rovira i Virgili, Reus, Spain and ICO, Hospital Trueta, Girona, Spain (Joan Brunet-Vidal); Boston: Massachusetts General Hospital, Boston, MA (Guang Yang); Brisbane: Queensland Institute of Medical Research (Nicholas Martin, David Whiteman, Adele Green) and Queensland Cancer Fund (Joanne Aitken), Brisbane, Australia; Emilia-Romagna: Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy (Paola Minghetti); Genoa: Dipartimento di Oncologia, Biologia e Genetica, Universita degli Studi di Genova, Vle Benedetto XV, 6, 16132 Genova, Italy (Michela Mantelli, Lorenza Pastorino, Sabina Nasti, Sara Gargiulo), Istituto Nazionale per la Ricerca sul Cancro (IST), Largo Rosanna Benzi, 10, 16132 Genova, Italy (Sara Gliori); Leeds: Genetic Epidemiology Division, Cancer Research UK Clinical Centre, Leeds (Sushila Mistry, Juliette Randerson-Moor); Leiden: Leiden University Medical Center (Femke A de Snoo, Jeanet AC ter Huurne, Jasper van der Rhee, Leny van Mourik, Frans van Nieuwpoort), STOET, The Netherlands Foundation for the Detection of Hereditary Tumors (Clasine van der Drift), Leiden, The Netherlands; Paris: Service de Génétique, Institut Gustave Roussy, Villejuif (Brigitte Bressac-de Paillerets), AP-HP-Hopital Cochin, Université Réné Descartes, Paris (Marie-Francoise Avril), French Hereditary Melanoma Study Group: Drs F Grange, B Sassolas, F Boitier, J Chevrant-Breton, C Lasset, C Dugast, P Vabres, France; Philadelphia: Department of Genetics (Arupa Ganguly), Department of Dermatology (Michael Ming), Department of Pathology and Laboratory Medicine (Patricia Van Belle), University of Pennsylvania, Philadelphia, PA, USA;
Stockholm: Department of Oncology-Pathology, Karolinska Institute and Karolinska University Hospital Solna, Stockholm, Sweden (Anton Platz, Suzanne Egyhazi, Rainer Tuominen, Diana Linden); Sydney: Westmead Institute for Cancer Research, Sydney, Australia (Helen Schmid);
Tel-Aviv: Department of Dermatology (Alon Scope, Felix Pavlotsky), The Susanne Levy Oncogenetics Unit (Eitan Friedman), Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Israel; Utah: Department of Dermatology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT (Mark Eliason).
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