title: CDKN2A mutations and melanoma risk in the Icelandic population.
abstract: BACKGROUND
  Germline CDKN2A mutations have been observed in 20-40% of high risk, melanoma prone families; however, little is known about their prevalence in population based series of melanoma cases and controls.
  
  
  METHODS
  We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry ascertained melanoma cases and 691 population based controls from Iceland, a country in which the incidence of melanoma has increased rapidly.
  
  
  RESULTS
  We identified a novel germline variant, G89D, that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head and neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma.
  
  
  CONCLUSIONS
  This population based study of Icelandic melanoma cases and controls showed a frequency of disease related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consist of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population based estimates of CDKN2A mutation frequencies are available.
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiologyand Genetics/NCI/NIH/DHHS, Executive Plaza South, Room 7004, 6120 Executive Blvd MSC 7236, Bethesda, MD 20892-7236, USA. goldstea@exchange.nih.gov
authors.forename: A M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: S N
authors.initials: SN
authors.lastname: Stacey
authors.forename: J H
authors.initials: JH
authors.lastname: Olafsson
authors.forename: G F
authors.initials: GF
authors.lastname: Jonsson
authors.forename: A
authors.initials: A
authors.lastname: Helgason
authors.forename: P
authors.initials: P
authors.lastname: Sulem
authors.forename: B
authors.initials: B
authors.lastname: Sigurgeirsson
authors.forename: K R
authors.initials: KR
authors.lastname: Benediktsdottir
authors.forename: K
authors.initials: K
authors.lastname: Thorisdottir
authors.forename: R
authors.initials: R
authors.lastname: Ragnarsson
authors.forename: J
authors.initials: J
authors.lastname: Kjartansson
authors.forename: J
authors.initials: J
authors.lastname: Kostic
authors.forename: G
authors.initials: G
authors.lastname: Masson
authors.forename: K
authors.initials: K
authors.lastname: Kristjansson
authors.forename: J R
authors.initials: JR
authors.lastname: Gulcher
authors.forename: A
authors.initials: A
authors.lastname: Kong
authors.forename: U
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: T
authors.initials: T
authors.lastname: Rafnar
authors.forename: M A
authors.initials: MA
authors.lastname: Tucker
authors.forename: K
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000483:Alleles; D001315:Australia; D016022:Case-Control Studies; D005787:Gene Frequency; D019942:Genes, p16; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D008545:Melanoma / Q000453:epidemiology* / Q000235:genetics*; D009656:North America; D044382:Population Groups; D012307:Risk Factors