melanocytes contained morphologically normal melanosomes predominantly of stages I and II with minimal stage III. DOPA histochemistry demonstrated increased melanization of the melanosomes. In addition, and unique to HPS-3 melanocytes, numerous DOPA positive 50 nm vesicles and tubular elements were present throughout the cell body and dendrites. These results suggest that tyrosinase is aberrantly trafficked within HPS-3 melanocytes and responsible for the reduction in melanin synthesis. 4 Kumamoto, Japan UV light is regarded as a major pathogenic factor for melanoma. However, melanoma can arise in anatomic sites that are relatively or completely sun protected. We have analyzed 126 primary melanomas from anatomic sites in different sun exposure [skin with (n ¼ 30) or without (n ¼ 40) chronic sun damage (CSD), glabrous (non-hair bearing acral skin, n ¼ 36), and mucosa (n ¼ 20)] for DNA copy number aberrations using array CGH and for the mutational status in BRAF, NRAS, HRAS, and KRAS. We found significant differences in the type of genomic instability, regional DNA copy number changes, mutation frequencies in BRAF and NRAS between the four groups. Melanomas arising on the relatively or absolutely sun protected glabrous skin or mucosa, respectively, showed significantly a higher degree of chromosomal instability as assessed by the overall proportion of genome altered, copy number transitions in chromosomes, and total number of amplifications. Melanomas on glabrous skin showed higher frequencies of amplifications of the cyclin D1 locus, losses of 10p, and gains affecting 6p. Mucosal melanomas had higher frequencies of gains of 1q, and losses affecting 4q, 8p, 11p, 21q. When melanomas on the skin with or without CSD were compared, cases with no CSD had significantly more losses affecting 10q and gains of 20q, whereas cases with CSD showed more frequent losses of 4q, 11p, and gains of 22. Based on chromosomal aberrations alone samples could be correctly classified with 63% accuracy into the four groups.Mutations in BRAF were found more commonly in cases with no CSD (18/27 or 67%) and were significantly less frequent in other types (2/15 in CSD, 3/26 in glabrous, 1/17 in