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Cancer Manag Res. 2018 May 14;10:1143-1154. doi: 10.2147/CMAR.S155283. eCollection 2018.

MC1R variants as melanoma risk factors independent of at-risk phenotypic characteristics: a pooled analysis from the M-SKIP project.

Author information

Clinical Trial Center, Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori.
Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy.
Section of Epidemiology and Biostatistics, Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Ronald O. Perelman Department of Dermatology, New York University School of Medicine, NYU Langone Medical Center, New York, NY.
Division of Epidemiology and Community Health, University of Minnesota, MN.
Department of Cancer Epidemiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Department of Internal Medicine and Medical Specialties, University of Genoa.
IRCCS AOU San Martino-IST, Genoa, Italy.
Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua.
Department of Dermatology, University of L'Aquila, L'Aquila, Italy.
Department of Biochemistry, Molecular Biology, and Immunology, University of Murcia.
IMIB-Arrixaca, Murcia, Spain.
Department of Epidemiology, Richard M Fairbanks School of Public Health, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA.
School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.
Department of Social and Environmental Health Research, London School of Hygiene and Tropical Medicine, London, UK.



Melanoma represents an important public health problem, due to its high case-fatality rate. Identification of individuals at high risk would be of major interest to improve early diagnosis and ultimately survival. The aim of this study was to evaluate whether MC1R variants predicted melanoma risk independently of at-risk phenotypic characteristics.

Materials and methods:

Data were collected within an international collaboration - the M-SKIP project. The present pooled analysis included data on 3,830 single, primary, sporadic, cutaneous melanoma cases and 2,619 controls from seven previously published case-control studies. All the studies had information on MC1R gene variants by sequencing analysis and on hair color, skin phototype, and freckles, ie, the phenotypic characteristics used to define the red hair phenotype.


The presence of any MC1R variant was associated with melanoma risk independently of phenotypic characteristics (OR 1.60; 95% CI 1.36-1.88). Inclusion of MC1R variants in a risk prediction model increased melanoma predictive accuracy (area under the receiver-operating characteristic curve) by 0.7% over a base clinical model (P=0.002), and 24% of participants were better assessed (net reclassification index 95% CI 20%-30%). Subgroup analysis suggested a possibly stronger role of MC1R in melanoma prediction for participants without the red hair phenotype (net reclassification index: 28%) compared to paler skinned participants (15%).


The authors suggest that measuring the MC1R genotype might result in a benefit for melanoma prediction. The results could be a valid starting point to guide the development of scientific protocols assessing melanoma risk prediction tools incorporating the MC1R genotype.


cutaneous melanoma; genetic epidemiology; melanocortin 1 receptor; pigmentation; pooled analysis

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