title: MC1R variants increase melanoma risk in families with CDKN2A mutations: a meta-analysis.
abstract: OBJECTIVE
  We performed a meta-analysis to assess whether MC1R variants increase the risk of melanoma in CDKN2A mutation carriers of melanoma-prone families.
  
  
  METHODS
  Data from 96 CDKN2A-positive melanoma-prone families from seven independent populations of Europe, United States and Australia were included in the analysis. Summary risk estimates were calculated by random-effect models. We explored between-study heterogeneity and publication bias. Association between MC1R variants and age at diagnosis was assessed by the non-parametric Wilcoxon test.
  
  
  RESULTS
  CDKN2A mutation carriers with 1 MC1R variant showed a double melanoma risk as compared to CDKN2A mutation carriers without MC1R variants (Summary OR; 95%CI: 2.2; 1.1-4.5). MC1R heterozygous subjects had no significantly higher melanoma risk than wild-type subjects (1.6; 0.5-5.4) while carriers of multiple MC1R variants had a more than four-times higher melanoma risk (4.6; 1.3-16.4). Carriers of red hair colour (RHC) variants showed an increased melanoma risk with a Summary OR of 3.5 (95%CI: 1.3-9.9). CDKN2A mutation carriers with MC1R variants had a statistically significant lower median age at melanoma diagnosis than CDKN2A mutation carriers with no MC1R variants (37years versus 47years, p-value<0.0001).
  
  
  CONCLUSIONS
  MC1R variants significantly increase penetrance of CDKN2A mutations in melanoma-prone families, especially with respect to multiple MC1R variants and to RHC variants. A significant anticipation of melanoma diagnosis is observed in CDKN2A mutation carriers with MC1R variants.
authors.affiliation: Department of Dermatology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Fargnoli
authors.forename: Sara
authors.initials: S
authors.lastname: Gandini
authors.forename: Ketty
authors.initials: K
authors.lastname: Peris
authors.forename: Patrick
authors.initials: P
authors.lastname: Maisonneuve
authors.forename: Sara
authors.initials: S
authors.lastname: Raimondi
mesh_terms: D001315:Australia; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D016017:Odds Ratio; D010375:Pedigree; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*; D014481:United States
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D044102:Receptor, Melanocortin, Type 1