2-LOCUS LINKAGE ANALYSIS OF CUTANEOUS MALIGNANT MELANOMA DYSPLASTIC NEVI/

Previous linkage analyses of 19 cutaneous malignant melanoma/dysplasti c nevi (CMM/DN) kindreds showed significant evidence of linkage and he terogeneity to both chromosomes 1p and 9p, Five kindreds also showed e vidence of linkage (Z > 0.7) to both regions. To further examine these findings, we conducted two-trait-locus, two-marker-locus linkage anal ysis. We examined one homogeneity and one heterogeneity single-locus m odel (SL-Hom and SL-Het), and two two-locus (2L) models: an epistatic model (Ep), in which CMM was treated as a genuine 2L disease, and a he terogeneity model (Het), in which CMM could result from disease allele s at either locus. Both loci were modeled as autosomal dominant, The L OD scores for CMM alone were highest using the SL-Het model (Z = 8.48, theta = .0). There was much stronger evidence of linkage to chromosom e 9p than to 1p for CMM alone; the LOD scores were approximately two t imes greater on 9p than on 1p. The change in LOD scores from an evalua tion of CMM atone to CMM/DN suggested that a chromosome 1p locus (or l oci) contributed to both CMM and CMM/DN, whereas a 9p locus contribute d more to CMM alone. For both 2L models, the LOD scores from 1p were g reater for CMM/DN than for CMM alone (Ep: Z = 4.63 vs. 3.83; Het: 4.94 vs. 3.80, respectively). In contrast, for 9p, the LOD scores were sub stantially lower with CMM/DN than with CMM alone (Ep: 4.64 vs. 7.06; H et: 5.38 vs. 7.99, respectively). After conditioning on linkage to the other locus, only the 9p locus consistently showed significant eviden ce for linkage to CMM alone. Thus, the application of 2L models may be useful to help unravel the complexities of familial melanoma.