Localization of a novel melanoma susceptibility locus to 1p22

Elizabeth Gillanders, Sub Hang Hank Juo, Elizabeth A. Holland, MaryPat Jones, Derek Nancarrow, Diana Freas-Lutz, Raman Sood, Naeun Park, Mezbah Faruque, Carol Markey, Richard F. Kefford, Jane Palmer, Wilma Bergman, D. Timothy Bishop, Margaret A. Tucker, Brigitte Bressac-De Paillerets, Johan Hansson, Mitchell Stark, Nelleke Gruis, Julia Newton BishopAlisa M. Goldstein, Joan E. Bailey-Wilson, Graham J. Mann, Nicholas Hayward, Jeffrey Trent*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)

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 [θ] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (θ = 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 (θ = 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.

Original languageEnglish
Pages (from-to)301-313
Number of pages13
JournalAmerican Journal of Human Genetics
Volume73
Issue number2
DOIs
Publication statusPublished - 1 Aug 2003
Externally publishedYes

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