Localization of a novel melanoma susceptibility locus to 1p22.
Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.
Gillanders
Elizabeth
E
Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Juo
Suh-Hang Hank
SH
Holland
Elizabeth A
EA
Jones
MaryPat
M
Nancarrow
Derek
D
Freas-Lutz
Diana
D
Sood
Raman
R
Park
Naeun
N
Faruque
Mezbah
M
Markey
Carol
C
Kefford
Richard F
RF
Palmer
Jane
J
Bergman
Wilma
W
Bishop
D Timothy
DT
Tucker
Margaret A
MA
Bressac-de Paillerets
Brigitte
B
Hansson
Johan
J
Stark
Mitchell
M
Gruis
Nelleke
N
Bishop
Julia Newton
JN
Goldstein
Alisa M
AM
Bailey-Wilson
Joan E
JE
Mann
Graham J
GJ
Hayward
Nicholas
N
Trent
Jeffrey
J
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001315:Australia; D002648:Child; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D012878:Skin Neoplasms / Q000235:genetics*