LINKAGE ANALYSIS IN FAMILIAL MELANOMA KINDREDS TO MARKERS ON CHROMOSOME 6P

Malignant melanoma occurs as a familial cancer in 5%-10% of cases, whe re it segregates in a manner consistent with autosomal dominant inheri tance. Evidence from cytogenetics, fine mapping studies of deletions i n melanomas and recent linkage studies supports the location of a huma n melanoma predisposition gene on the short arm of chromosome 9. Evide nce also exists for a melanoma gene on Ip, indicating genetic heteroge neity for melanoma predisposition. Previous studies have also reported findings suggestive of linkage of some melanoma families to the HLA r egion on the short arm of chromosome 6 (6p), indicating the possibilit y of even greater heterogeneity. To further define the possible effect of a gene within the HLA region on melanoma susceptibility, we have t yped 7 simple tandem repeat polymorphisms (STRPs) from 6p in 16 Austra lian melanoma kindreds. Maximum 2-point LOD scores ranged from 1.13 (t heta = 0.2) to 2.03 (theta = 0.15) for 4 contiguous markers flanking t he HLA complex, and multi-point analysis gave a peak LOD score of 1.64 , 24 centimorgans telomeric to D6S109. However, extended haplotype ana lysis of these markers showed that a region between D6S105 and HLAF se gregated with melanoma in 5/16 families. These results are surprising given that the same cohort of families has previously been shown to be linked to chromosome 9. One interpretation of the current findings is that melanoma susceptibility in some families may result from a gene mapping within the HLA region of chromosome 6p. (C) 1995 Wiley-Liss, I nc.