Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents.
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.
Goldstein
Alisa M
AM
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892-7236, USA. goldstea@exchange.nih.gov
Chan
May
M
Harland
Mark
M
Hayward
Nicholas K
NK
Demenais
Florence
F
Bishop
D Timothy
DT
Azizi
Esther
E
Bergman
Wilma
W
Bianchi-Scarra
Giovanna
G
Bruno
William
W
Calista
Donato
D
Albright
Lisa A Cannon
LA
Chaudru
Valerie
V
Chompret
Agnes
A
Cuellar
Francisco
F
Elder
David E
DE
Ghiorzo
Paola
P
Gillanders
Elizabeth M
EM
Gruis
Nelleke A
NA
Hansson
Johan
J
Hogg
David
D
Holland
Elizabeth A
EA
Kanetsky
Peter A
PA
Kefford
Richard F
RF
Landi
Maria Teresa
MT
Lang
Julie
J
Leachman
Sancy A
SA
MacKie
Rona M
RM
Magnusson
Veronica
V
Mann
Graham J
GJ
Bishop
Julia Newton
JN
Palmer
Jane M
JM
Puig
Susana
S
Puig-Butille
Joan A
JA
Stark
Mitchell
M
Tsao
Hensin
H
Tucker
Margaret A
MA
Whitaker
Linda
L
Yakobson
Emanuel
E
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*
D019941:Cyclin-Dependent Kinase Inhibitor p16