High expression of DNA repair pathways is associated with metastasis in melanoma patients

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 ¼ 10 À14 ) and the DNA repair pathways (P ¼ 10 À16 ). 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 errorfree 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.

O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

“…The increased haematological toxicity is indicative of the importance of O 6 -meG, and it is reasonable to speculate that factors downstream of O 6 -meG, such as MMR and anti-apoptotic factors, and/or other TMZ-induced DNA lesions may have decisive functions in the resistance of melanoma to TMZ. In addition, with respect to DNA repair processes, recent studies show that a wide range of such processes are upregulated in poor prognosis melanoma (Kauffmann et al, 2008). More specifically, the effects of targeting the base excision repair pathway by blocking the processing of apurinic sites (Yan et al, 2007) or single-strand breaks through inhibition of poly-ADP-ribose polymerase activity (Naumann et al, 2009) are currently being assessed in clinical trials.…”

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

“…Cells can become resistant through enhanced ability to remove DNA adducts (Martin et al, 2008). Elevated expression of DNA repair genes has been reported in primary melanomas that subsequently went on to metastasize when compared with non-recurrent primary tumours (Kauffmann et al, 2008). This increased expression could contribute to the extreme resistance shown by melanoma to conventional DNA-damaging chemotherapeutics.…”

Circulating Melanoma Cells

“…VEGFR, ERBB2, TGF-betaR), the Ras / Raf / MEK / ERK pathway, the PI3K / Akt / PTEN / mTOR pathway, cell cycle regulation pathways (Rb / p53 / p16INKA / p14ARF / HDM2), epigenetic gene expression regulation and DNA repair pathways (DNA methylation, histone acetylation, RNA interference), apoptotic pathways (e.g. death receptors: FAS, TRAILR, TNFR; mitochondrial pathway: Bcl2 family), common apoptosis effectors, protein chaperoning, degradation (HSP, proteasome) 25,108,109 and epithelial to mesenchymal transition (reviewed in 110 ). A thorough screening of CTCs from metastatic melanoma patients for these activated pathways needs to be performed so as to establish their involvement in CTC survival, proliferation and intraand extravasation.…”