ORIGINAL ARTICLE

¹ Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA
² Genetic Epidemiology Division, Cancer Research UK Clinical Centre, Leeds, UK
³ Queensland Institute of Medical Research, Brisbane, Queensland, Australia
⁴ INSERM, U794, Université d’Evry, Evry, France
⁵ Department of Dermatology, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
⁶ Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
⁷ Department of Oncology, Biology, and Genetics, University of Genova, Genova, Italy
⁸ Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy
⁹ Department of Medical Informatics, University of Utah School of Medicine, Salt Lake City, Utah, USA
¹⁰ Service de Génétique, Institut Gustave Roussy, Villejuif, France
¹¹ Dermatology Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS (Institut de Investigació Biomèdica August Pi Suñe), Barcelona, Spain
¹² Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
¹³ Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, DHHS, Baltimore, Maryland, USA
¹⁴ Department of Oncology-Pathology, Karolinska Institute and Karolinska University Hospital Solna, Stockholm, Sweden
¹⁵ Departments of Medicine and Medical Biophysics, University of Toronto, Toronto, Ontaria, Canada
¹⁶ Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, New South Wales, Australia
¹⁷ Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
¹⁸ Department of Medical Genetics, University of Glasgow, Glasgow, UK
¹⁹ Department of Dermatology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
²⁰ Genetics Service, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS (Institut de Investigació Biomèdica August Pi Suñe), Barcelona, Spain
²¹ Wellman Center for Photomedicine, Department of Dermatology and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA
²² Molecular Cell Biology Laboratory, Department of Internal Medicine C, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
²³ Lund Cancer Center Department of Oncology, University Hospital, Lund, Sweden

Correspondence to:
Dr A M Goldstein
Genetic Epidemiology Branch/NCI/NIH/DHHS, Executive Plaza South, Room 7004, 6120 Executive Blvd. MSC 7236, Bethesda, MD 20892-7236, USA; goldstea{at}exchange.nih.gov

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.

Abbreviations: ARF, alternate reading frame; CMM, cutaneous malignant melanoma; MPM, multiple primary melanoma

Keywords: melanoma; CDKN2A; multiple primary melanomas; pancreatic cancer

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