title: A large French case-control study emphasizes the role of rare Mc1R variants in melanoma risk.
abstract: BACKGROUND
  The MC1R gene implicated in melanogenesis and skin pigmentation is highly polymorphic. Several alleles are associated with red hair and fair skin phenotypes and contribute to melanoma risk.
  
  
  OBJECTIVE
  This work aims to assess the effect of different classes of MC1R variants, notably rare variants, on melanoma risk. Methods. MC1R coding region was sequenced in 1131 melanoma patients and 869 healthy controls. MC1R variants were classified as RHC (R) and non-RHC (r). Rare variants (frequency < 1%) were subdivided into two subgroups, predicted to be damaging (D) or not (nD).
  
  
  RESULTS
  Both R and r alleles were associated with melanoma (OR = 2.66 [2.20-3.23] and 1.51 [1.32-1.73]) and had similar population attributable risks (15.8% and 16.6%). We also identified 69 rare variants, of which 25 were novel. D variants were strongly associated with melanoma (OR = 2.38 [1.38-4.15]) and clustered in the same MC1R domains as R alleles (intracellular 2, transmembrane 2 and 7).
  
  
  CONCLUSIONS
  This work confirms the role of R and r alleles in melanoma risk in the French population and proposes a novel class of rare D variants as important melanoma risk factors. These findings may improve the definition of high-risk subjects that could be targeted for melanoma prevention and screening.
authors: INSERM U976, Centre de Recherche sur la Peau, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France ; Laboratoire de Génétique, Hôpital Bichat Claude Bernard, APHP, IFR02, Université Paris 7, 46 rue Henri Hucahrd, 75018 Paris, France.
authors: Hui-Han
authors: HH
authors: Hu
authors: Laboratoire de Génétique, Hôpital Bichat Claude Bernard, APHP, IFR02, Université Paris 7, 46 rue Henri Hucahrd, 75018 Paris, France.
authors: Mériem
authors: M
authors: Benfodda
authors: INSERM U976, Centre de Recherche sur la Peau, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France.
authors: Nicolas
authors: N
authors: Dumaz
authors: UMR S738, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France.
authors: Steven
authors: 0000-0001-5714-7597
authors: S
authors: Gazal
authors: INSERM U976, Centre de Recherche sur la Peau, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France ; Service de Dermatologie, Hôpital Bichat Claude Bernard, APHP, Université Paris 7, 46 rue Henri Hucahrd, 75018 Paris, France.
authors: Vincent
authors: V
authors: Descamps
authors: Laboratoire de Génétique, Hôpital Bichat Claude Bernard, APHP, IFR02, Université Paris 7, 46 rue Henri Hucahrd, 75018 Paris, France.
authors: Agnès
authors: A
authors: Bourillon
authors: INSERM U976, Centre de Recherche sur la Peau, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France ; Service de Dermatologie, Hôpital Saint Louis, APHP, Université Paris 7, 1 Avenue Claude Vellefaux, 75010 Paris, France.
authors: Nicole
authors: N
authors: Basset-Seguin
authors: Laboratoire de Génétique, Hôpital Bichat Claude Bernard, APHP, IFR02, Université Paris 7, 46 rue Henri Hucahrd, 75018 Paris, France.
authors: Angélique
authors: A
authors: Riffault
authors: Service de Dermatologie, CHU Bordeaux, Université V Segalen Bordeaux 2, 12 rue Dubernat 33404 Bordeaux, France ; INSERM U876, 146 rue Leo Saignat, 33076 Bordeaux, France.
authors: Khaled
authors: K
authors: Ezzedine
authors: INSERM U976, Centre de Recherche sur la Peau, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France ; Service de Dermatologie, Hôpital Saint Louis, APHP, Université Paris 7, 1 Avenue Claude Vellefaux, 75010 Paris, France.
authors: Martine
authors: M
authors: Bagot
authors: INSERM U976, Centre de Recherche sur la Peau, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France ; Service de Dermatologie, Hôpital Saint Louis, APHP, Université Paris 7, 1 Avenue Claude Vellefaux, 75010 Paris, France.
authors: Armand
authors: 0000-0002-0409-2497
authors: A
authors: Bensussan
authors: Service de Dermatologie, Hôpital Ambroise Paré, APHP, 9 Avenue Charles-de-Gaulle, 92100 Boulogne Billancourt, France ; Université Saint Quentin en Yvelines, 55 Avenue de Paris, 78000 Versailles, France.
authors: Philippe
authors: P
authors: Saiag
authors: Laboratoire de Génétique, Hôpital Bichat Claude Bernard, APHP, IFR02, Université Paris 7, 46 rue Henri Hucahrd, 75018 Paris, France.
authors: Bernard
authors: B
authors: Grandchamp
authors: INSERM U976, Centre de Recherche sur la Peau, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France ; Laboratoire de Génétique, Hôpital Bichat Claude Bernard, APHP, IFR02, Université Paris 7, 46 rue Henri Hucahrd, 75018 Paris, France.
authors: Nadem
authors: N
authors: Soufir
mesh_terms: D016022:Case-Control Studies; D005602:France; D020022:Genetic Predisposition to Disease; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017434:Protein Structure, Tertiary; D044102:Receptor, Melanocortin, Type 1 / Q000737:chemistry / Q000235:genetics*; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D044102:Receptor, Melanocortin, Type 1