title: Germline MC1R status influences somatic mutation burden in melanoma.
abstract: The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene. These alleles are also linked to red hair, freckling, and sun sensitivity, all of which are known melanoma phenotypic risk factors. Here we report that in melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant count associated with the presence of an R allele is estimated to be 42% (95% CI, 15-76%) higher than that among persons without an R allele. This figure is comparable to the expected mutational burden associated with an additional 21 years of age. We also find significant and similar enrichment of non-C>T mutation classes supporting a role for additional mutagenic processes in melanoma development in individuals carrying R alleles.
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.|Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Campus Juriquilla, Boulevard Juriquilla 3001, Santiago de Querétaro 76230, Mexico.
authors.forename: Carla Daniela
authors.initials: CD
authors.lastname: Robles-Espinoza
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.|The Cancer Genome Project, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Nicola D
authors.initials: ND
authors.lastname: Roberts
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine. Boston, Massachusetts 02118, USA.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Chen
authors.affiliation: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.|Division of Population Health Sciences, Royal College of Surgeons in Ireland, Lower Mercer Street, Dublin 2, Ireland.
authors.forename: Finbarr P
authors.identifier: http://orcid.org/0000-0001-5561-485X
authors.initials: FP
authors.lastname: Leacy
authors.affiliation: The Cancer Genome Project, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06519, USA.
authors.forename: Natapol
authors.identifier: http://orcid.org/0000-0002-3833-0537
authors.initials: N
authors.lastname: Pornputtapong
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06519, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06519, USA.|Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, Connecticut 06519, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Krauthammer
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine. Boston, Massachusetts 02118, USA.
authors.forename: Rutao
authors.initials: R
authors.lastname: Cui
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: D
authors.identifier: http://orcid.org/0000-0002-8752-8785
authors.initials: D
authors.lastname: Timothy Bishop
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D018095:Germ-Line Mutation / Q000235:genetics*; D006200:Hair Color; D006258:Head and Neck Neoplasms / Q000235:genetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008548:Melanosis; D008875:Middle Aged; D009154:Mutation; D000067552:Mutation Accumulation; D009361:Neoplasm Invasiveness; D020641:Polymorphism, Single Nucleotide; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D012880:Skin Pigmentation
chemical_list: D044102:Receptor, Melanocortin, Type 1