CDKN2A germline mutations in individuals with cutaneous malignant melanoma.
Cyclin-dependent kinase inhibitor type 2A (CDKN2A) has been identified as a major melanoma susceptibility gene based on the presence of germline mutations in high-risk melanoma families. In this study, we sought to identify and characterize the spectrum of CDKN2A mutations affecting p16 inhibitor of cyclin-dependent kinase type 4 (INK4a) in individuals with melanoma using a population-based study design. DNA samples from 1189 individuals with incident multiple primary melanoma (MPM) and 2424 with incident single primary melanoma unselected for family history of melanoma were available for screening of CDKN2A (p16INK4a) mutations. Variants were classified for functional impact based on intragenic position, existing functional data, sequence, and structural analysis. The impact of individual mutations and functional groupings was assessed by comparing frequencies in cases of MPM versus cases with a single first primary melanoma, and by comparing the reported incidence rates in first-degree relatives. Our results show that mutations occur infrequently in these high-risk groups, and that they occur mainly in exons 1alpha and 2. Rare coding variants with putative functional impact are observed to increase substantially the risk of melanoma. With the exception of the variant in position -34 of CDKN2A of known functional consequence, the remaining rare variants in the non-coding region have no apparent impact on risk.
Orlow
Irene
I
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. orlowi@mskcc.org
Begg
Colin B
CB
Cotignola
Javier
J
Roy
Pampa
P
Hummer
Amanda J
AJ
Clas
Brian A
BA
Mujumdar
Urvi
U
Canchola
Rebecca
R
Armstrong
Bruce K
BK
Kricker
Anne
A
Marrett
Loraine D
LD
Millikan
Robert C
RC
Gruber
Stephen B
SB
Anton-Culver
Hoda
H
Zanetti
Roberto
R
Gallagher
Richard P
RP
Dwyer
Terence
T
Rebbeck
Timothy R
TR
Kanetsky
Peter A
PA
Wilcox
Homer
H
Busam
Klaus
K
From
Lynn
L
Berwick
Marianne
M
D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000502:physiology; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000503:physiopathology; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics* / Q000503:physiopathology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm