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Digital Karyotyping Reveals Frequent Inactivation of the dystrophin/DMD Gene in Malignant Melanoma

Henrike Körner, Alexey Epanchintsev, Carola Berking, Beatrice Schuler-Thurner, Michael R. Speicher, Antje Menssen and Heiko Hermeking

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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.

Authors

Henrike Körner

Max-Planck-Institute of Biochemistry, Munich, Germany

Alexey Epanchintsev

Max-Planck-Institute of Biochemistry, Martinsreid, Germany

Carola Berking

University, Frauenlobstr. Munich, Germany

Beatrice Schuler-Thurner

University Hospital of Erlangen, Erlangen, Germany

Michael R. Speicher

Medical University of Graz, Graz, Austria

Antje Menssen

Max-Planck-Institute of Biochemistry, Martinsried, Germany

Heiko Hermeking

Max-Planck-Institute of Biochemistry, Martinsried, Germany

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.