title: Localization of a novel melanoma susceptibility locus to 1p22.
abstract: 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.
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gillanders
authors.forename: Suh-Hang Hank
authors.initials: SH
authors.lastname: Juo
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holland
authors.forename: MaryPat
authors.initials: M
authors.lastname: Jones
authors.forename: Derek
authors.initials: D
authors.lastname: Nancarrow
authors.forename: Diana
authors.initials: D
authors.lastname: Freas-Lutz
authors.forename: Raman
authors.initials: R
authors.lastname: Sood
authors.forename: Naeun
authors.initials: N
authors.lastname: Park
authors.forename: Mezbah
authors.initials: M
authors.lastname: Faruque
authors.forename: Carol
authors.initials: C
authors.lastname: Markey
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Jane
authors.initials: J
authors.lastname: Palmer
authors.forename: Wilma
authors.initials: W
authors.lastname: Bergman
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.forename: Mitchell
authors.initials: M
authors.lastname: Stark
authors.forename: Nelleke
authors.initials: N
authors.lastname: Gruis
authors.forename: Julia Newton
authors.initials: JN
authors.lastname: Bishop
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hayward
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Trent
mesh_terms: 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*