Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study.
BACKGROUND
Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.


METHODS
We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.


RESULTS
Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10(-6) ≤ P ≤ .02).


CONCLUSIONS
Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.
Demenais
F
F
INSERM U946, Fondation Jean-Dausset-CEPH , 27 rue Juliette Dodu, 75010 Paris, France. florence.demenais@inserm.fr
Mohamdi
H
H
Chaudru
V
V
Goldstein
A M
AM
Newton Bishop
J A
JA
Bishop
D T
DT
Kanetsky
P A
PA
Hayward
N K
NK
Gillanders
E
E
Elder
D E
DE
Avril
M F
MF
Azizi
E
E
van Belle
P
P
Bergman
W
W
Bianchi-Scarrà
G
G
Bressac-de Paillerets
B
B
Calista
D
D
Carrera
C
C
Hansson
J
J
Harland
M
M
Hogg
D
D
Höiom
V
V
Holland
E A
EA
Ingvar
C
C
Landi
M T
MT
Lang
J M
JM
Mackie
R M
RM
Mann
G J
GJ
Ming
M E
ME
Njauw
C J
CJ
Olsson
H
H
Palmer
J
J
Pastorino
L
L
Puig
S
S
Randerson-Moor
J
J
Stark
M
M
Tsao
H
H
Tucker
M A
MA
van der Velden
P
P
Yang
X R
XR
Gruis
N
N
D000328:Adult; D001315:Australia; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005060:Europe; D005260:Female; D019942:Genes, p16; D006200:Hair Color; D006579:Heterozygote; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D009506:Nevus / Q000150:complications / Q000235:genetics; D009656:North America; D010641:Phenotype; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics*; D012880:Skin Pigmentation; D013471:Sunburn / Q000150:complications; D044465:White People / Q000235:genetics
D019941:Cyclin-Dependent Kinase Inhibitor p16; D044102:Receptor, Melanocortin, Type 1