High expression of DNA repair pathways is associated with metastasis in melanoma patients
High expression of DNA repair pathways is associated with metastasis in melanoma patients
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DOI：
10.1038/sj.onc.1210700
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发表时间：
2008-01-24
期刊：
影响因子：
8
通讯作者：
Sarasin, A.
中科院分区：
文献类型：
--
作者：
Kauffmann, A.;Rosselli, F.;Sarasin, A.
我们已经确定了人类原发性恶性黑色素瘤与远处转移和预后不良相关的基因谱特征。我们通过观察整个生物学途径而不是单个基因来分析差异基因表达。在与转移进展相关的最重要的途径中，我们发现了DNA复制（P = 10（-14））和DNA修复途径（P = 10（-16））。我们集中分析了DNA修复，发现在234个基因中，有48个基因与转移进展相关。这些基因基本上属于允许恢复由于自发阻断或诱导的DNA损伤而停滞的复制叉的途径。由于几乎所有这些差异表达的修复基因在预后不良的原发性肿瘤中过表达，我们推测将转移的原发性黑色素瘤细胞试图以快速和无错误的模式复制。与从黑素细胞到原发性黑色素瘤的进展相反，遗传稳定性似乎是黑色素瘤细胞引起远处转移所必需的。这种修复基因的过度表达很好地解释了转移性黑色素瘤对化疗和放疗的非凡抵抗力。我们的研究结果可能为发现对人类转移性黑色素瘤有活性的药物开辟一条新的途径。
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.