Abstract
We have identified a gene-profile signature for human primary malignant melanoma associated with metastasis to distant sites and poor prognosis. We analyse the differential gene expression by looking at whole biological pathways rather than individual genes. Among the most significant pathways associated with progression to metastasis, we found the DNA replication (P=10−14) and the DNA repair pathways (P=10−16). We concentrated our analysis on DNA repair and found that 48 genes of this category, among a list of 234 genes, are associated with metastatic progression. These genes belong essentially to the pathways allowing recovery of stalled replication forks due to spontaneous blockage or induced DNA lesions. Because almost all these differentially expressed repair genes were overexpressed in primary tumors with bad prognosis, we speculate that primary melanoma cells that will metastasize try to replicate in a fast and error-free mode. In contrast to the progression from melanocytes to primary melanoma, genetic stability appears to be necessary for a melanoma cell to give rise to distant metastasis. This overexpression of repair genes explains nicely the extraordinary resistance of metastatic melanoma to chemo- and radio-therapy. Our results may open a new avenue for the discovery of drugs active on human metastatic melanoma.
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Acknowledgements
The authors thank the Institut Gustave Roussy, and particularly Professors Gilbert Lenoir and Thomas Tursz for their constant interest in this work and their financial support. Grants were obtained from the ‘Cancéropole Ile-de–France’ and the INCa (Paris, France). AK got a fellowship from the French Ministry of National Education and Research (University Paris VII Denis Diderot, France). We thank Stefan Michiels and Dr Leela Daya-Grosjean for their critical reading of the manuscript.
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Availability: http://www.ebi.ac.uk/arrayexpressE-TABM-1 IGR_ MELANOMA_STUDYE-TABM-2 IGR_MELANOMA_VALID
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Kauffmann, A., Rosselli, F., Lazar, V. et al. High expression of DNA repair pathways is associated with metastasis in melanoma patients. Oncogene 27, 565–573 (2008). https://doi.org/10.1038/sj.onc.1210700
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DOI: https://doi.org/10.1038/sj.onc.1210700
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