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Multiple metastases from cutaneous malignant melanoma patients may display heterogeneous genomic and epigenomic patterns

Harbst, Katjaa c; Staaf, Johana c; Måsbäck, Annad; Olsson, Håkana; Ingvar, Christianb; Vallon-Christersson, Johana c; Ringnér, Markusa c; Borg, Åkea c e; Jönsson, Görana c

doi: 10.1097/CMR.0b013e32833b7c7c
ORIGINAL ARTICLES: Translational research

Disseminated melanoma is an aggressive disease with fatal outcome. Better understanding of the underlying biology is needed to find effective treatment. We applied microarray-based comparative genomic hybridization, gene expression and CpG island methylation analysis of primary tumors and multiple metastases from five melanoma patients with the aim of analyzing the molecular patterns of melanoma progression. Epigenetic profiling showed that the multiple metastases after a single primary melanoma share similar methylation patterns for many genes, although differences in methylation between the lesions were evident for several genes, example, PTEN, TFAP2C, and RARB. In addition, DNA copy number and global gene expression profiles of tumors from individual patients were highly similar, confirming common origin of metastases. Some of the identified genomic aberrations, for example, gain of chromosome 6p and loss of chromosomes 6q and 10, persisted during progression, indicating early changes highly important for melanoma development. Homozygous deletions at 3p26.1 and 6q23.2–q23.3 appeared in two consecutive metastases originating from the same primary tumor, respectively, in a mutually exclusive manner that provides evidence for two genetically different subclones. However, in another case, the similarity of the copy number aberrations in subsequent metastatic lesions suggests sequential metastatic development through the clonal evolution. These data are further corroborated by a switch in CDH1 and CDH2 expression between metastases from the same patient. In conclusion, our results provide evidence for different models of metastatic progression in melanoma.

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Departments of aOncology

bSurgery, Clinical Sciences

cCREATE Health Strategic Center for Translational Cancer Research

dDepartment of Pathology

eLund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden

Correspondence to Göran Jönsson, Department of Oncology, Lund University, SE-221 85 Lund, Sweden

Tel: +46 46 2221444; fax: +46 46 147327;

e-mail: goran_b.jonsson@med.lu.se

Received 19 November 2009 Accepted 23 April 2010

All supplementary data are available directly from the authors.

© 2010 Lippincott Williams & Wilkins, Inc.