title: Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree.
abstract: BACKGROUND
  Oculocutaneous albinism type 2 (OCA2) is caused by mutations of the OCA2 gene. Individuals affected by OCA2 as well as other types of albinism are at a significantly increased risk for sun-induced skin-cancers, including malignant melanoma (MM).
  
  
  OBJECTIVE
  To identify the molecular etiology of oculocutaneous albinism in a previously uncharacterized melanoma pedigree and to investigate the relationship between two OCA2 variants and melanoma predisposition in this pedigree.
  
  
  METHODS
  DNA and RNA were isolated from the peripheral blood of seven patients in a familial melanoma pedigree. Electron microscopy was performed on the individual with clinical oculocutaneous albinism. OCA2, TYRP1, MC1R, CDKN2A/p16, CDKN2A/p19ARF, and CDK4 genes were sequenced in affected individuals. The relationship between OCA2 variants and melanoma was assessed using a pedigree likelihood-based method.
  
  
  RESULTS
  The proband was determined to be an OCA2 compound heterozygous mutation carrier with a previously reported conservative missense mutation (V443I) and a novel non-conservative missense mutation (L734R). The pedigree contained individuals diagnosed with both cutaneous and iris melanoma. Based on co-segregation analysis, the odds of these OCA2 variants being high penetrance loci for melanoma was: 1.3-to-1 if we include the iris melanoma as affected and 6.5-to-1 if we only consider cutaneous melanoma as affected.
  
  
  CONCLUSIONS
  The discovery of this novel OCA2 variant adds to the body of evidence on the detrimental effects of OCA2 gene mutations on pigmentation, supports existing GWAS data on the relevance of the OCA2 gene in melanoma predisposition, and may ultimately assist in the development of targeted molecular therapies in the treatment of OCA and melanoma.
authors.affiliation: Huntsman Cancer Institute and Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Hawkes
authors.forename: Pamela B
authors.initials: PB
authors.lastname: Cassidy
authors.forename: Prashiela
authors.initials: P
authors.lastname: Manga
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Boissy
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
authors.forename: Lisa
authors.initials: L
authors.lastname: Cannon-Albright
authors.forename: Scott R
authors.initials: SR
authors.lastname: Florell
authors.forename: Sancy A
authors.initials: SA
authors.lastname: Leachman
mesh_terms: D016115:Albinism, Oculocutaneous / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D026901:Membrane Transport Proteins; C489600:OCA2 protein, human