| Abstract: | Malignant melanoma is still poorly understood at the genomic level. Recently, a new technique for the high-resolution analysis of copy number changes named digital karyotyping was introduced. This approach is derived from SAGE (serial analysis of gene expression) and allows the detection of genomic amplifications and deletions, which are indicative of oncogenes and tumor suppressor genes. Four human melanoma cell lines were subjected to analysis by digital karyotyping. 828,780 genomic tags were generated and analysed quantitatively. Thereby, we identified a somatic, homozygous deletion of 570 kbp removing exons 3-29 of the dystrophin (DMD, Duchenne muscular dystrophy) gene. Analysis of DMD in 51 melanoma cell lines further revealed a homozygous and a hemizygous deletion in DMD. Furthermore, DMD mRNA expression was down-regulated with respect to primary melanocytes and accompanied by loss of DMD protein expression in 38 of 55 (69%) and a significant reduction in 10 of 55 (18%) melanoma cell lines. Sequence analysis of DMD cDNAs in 37 melanoma cell lines revealed 6 new sequence variants with a significantly lower frequency than previously described DMD polymorphisms, which may affect dystrophin function. Knock-down of DMD enhanced migration and invasion, whereas re-expression of DMD attenuated migration and induced a senescent phenotype in melanoma cell lines. Taken together, our results suggest that inactivation of DMD is involved in the pathogenesis of malignant melanoma. Loss of DMD may critically change the migratory and proliferative capacity of melanocytes. |
