title: Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents.
abstract: BACKGROUND
  The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer.
  
  
  METHODS
  These four features were examined in 385 families with > or =3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents.
  
  
  RESULTS
  Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, > or =2 patients with MPM, median age at melanoma diagnosis < or =40 years and > or =6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only > or =1 patient with MPM and age at diagnosis < or =40 years simultaneously predicted the mutation risk.
  
  
  CONCLUSIONS
  The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892-7236, USA. goldstea@exchange.nih.gov
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: May
authors.initials: M
authors.lastname: Chan
authors.forename: Mark
authors.initials: M
authors.lastname: Harland
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: Esther
authors.initials: E
authors.lastname: Azizi
authors.forename: Wilma
authors.initials: W
authors.lastname: Bergman
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bianchi-Scarra
authors.forename: William
authors.initials: W
authors.lastname: Bruno
authors.forename: Donato
authors.initials: D
authors.lastname: Calista
authors.forename: Lisa A Cannon
authors.initials: LA
authors.lastname: Albright
authors.forename: Valerie
authors.initials: V
authors.lastname: Chaudru
authors.forename: Agnes
authors.initials: A
authors.lastname: Chompret
authors.forename: Francisco
authors.initials: F
authors.lastname: Cuellar
authors.forename: David E
authors.initials: DE
authors.lastname: Elder
authors.forename: Paola
authors.initials: P
authors.lastname: Ghiorzo
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Gillanders
authors.forename: Nelleke A
authors.initials: NA
authors.lastname: Gruis
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.forename: David
authors.initials: D
authors.lastname: Hogg
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holland
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.forename: Julie
authors.initials: J
authors.lastname: Lang
authors.forename: Sancy A
authors.initials: SA
authors.lastname: Leachman
authors.forename: Rona M
authors.initials: RM
authors.lastname: MacKie
authors.forename: Veronica
authors.initials: V
authors.lastname: Magnusson
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: Julia Newton
authors.initials: JN
authors.lastname: Bishop
authors.forename: Jane M
authors.initials: JM
authors.lastname: Palmer
authors.forename: Susana
authors.initials: S
authors.lastname: Puig
authors.forename: Joan A
authors.initials: JA
authors.lastname: Puig-Butille
authors.forename: Mitchell
authors.initials: M
authors.lastname: Stark
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.forename: Linda
authors.initials: L
authors.lastname: Whitaker
authors.forename: Emanuel
authors.initials: E
authors.lastname: Yakobson
mesh_terms: D001315:Australia / Q000453:epidemiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005260:Female; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D015994:Incidence; D008297:Male; D008545:Melanoma / Q000453:epidemiology / Q000235:genetics*; D009656:North America / Q000453:epidemiology; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16