Gene expression profiling of primary cutaneous melanoma and clinical outcome: role of DNA repair genes in metastasis development Gene expression profiling data for human primary cutaneous mel- anomas are scarce because of the lack of retrospective collections of frozen tumors. To identify differentially expressed genes that may be involved in melanoma progression and prognosis, we investigated the relationship between gene expression profiles and clinical outcome in a cohort of patients with primary melanoma. Labeled complementary RNA (cRNA) from each tissue sample was hybridized to a pangenomic 44K 60-mer oligonucleotide microarray. Class comparison and class prediction analyses were performed to identify genes whose expression in primary melan- omas was associated with 4-year distant metastasis–free survival among 58 patients with at least 4 years of follow-up, distant metastasis, or death. Survival was analyzed with a Cox multivari- able model and stratified log-rank test. All statistical tests were two-sided. We identified 254 genes that were associated with dis- tant metastasis-free survival of patients with primary melanoma. These 254 genes include genes involved in activating DNA repli- cation origins, such as minichromosome maintenance genes and geminin (J Natl Cancer Inst 2006, 98, 472–482). Numerous genes involved in the maintenance and recovery of stalled replication forks are overexpressed in primary melanomas that will give rise to distant metastasis. This high level of repair genes is probably linked to the extraordinary resistance of melanoma metastases to any chemo- or radio-therapy. These genes may shed light on the molecular mechanisms underlying poor prognosis in melanoma patients. MacKie R M, Bray C A, Hole D J et al. Incidence of and survival from malignant melanoma in Scotland: an epidemiological study. Lancet 2002: 360: 587–591. This paper aimed to assess the incidence and survival of primary cutaneous malignant melanoma in Scotland, UK. This report, that is universally applicable, described the very big increase in melanoma incidence for both men and women in the last 25 years. Whitfield M L, George L K, Grant G D, Perou C M. Common markers of proliferation. Nat Rev Cancer 2006: 6: 99–104. This review analyzed the genes differently expressed in tumor sam- ples versus normal tissue as compared by microarray data. Most of these genes are implicated in cellular proliferation (cell cycle, cell division, DNA replication, DNA metabolism) and are often associated with poor prognosis in cancer patients. These cell- cycle-regulated genes provided the biomarkers of proliferation for clinical diagnostics and cancer outcome. Clark E A, Golub T R, Lander E S, Hynes R O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 2000: 406: 532–535. Using DNA microarrays, the authors defined a pattern of gene expression associated with the switch from primary melanoma to highly metastatic melanoma cells. The small GTPase RhoC, when overexpressed, appears to enhance metastatic via tumor cell inva- sion. Pavey S, Johansson P, Packer L et al. Microarray expression pro- filing in melanoma reveals a BRAF mutation signature. Oncogene 2004: 23: 4060–4067. The BRAF gene is mutated in 50–70% of melanoma cells in cul- ture and in sporadic spontaneous melanomas. The authors des- cribed a 83-gene signature to discriminate between BRAF mutant and wild-type samples. Some genes are involved in a generalized mitogen-activated protein kinase activation. Michiels S, Koscielny S, Hill C. Prediction of cancer outcome with microarrays: a multiple random validation strategy. Lancet 2005: 365: 488–492. The authors described a new strategy to analyze the data from microarray gene-expression profiling. They developed original training and validation assays using multiple random sets to esti- mate the stability of the molecular gene signature and the propor- tion of misclassification. This paper indicates clearly that published microarray data should be cautiously reexamined. Ramaswamy S, Ross K N, Lander E S, Golub T R. A molecular signature of metastasis in primary solid tumors. Nat Genet 2003: 33: 49–54. Using gene expression profiling, the authors showed clearly the existence of a signature that differentiated primary from meta- static adenocarcinomas. Primary solid tumors carrying this signa- ture were most likely to be associated with metastasis and poor clinical outcome. This result suggests that the metastatic potential is encoded in the bulk of primary tumors. Bittner M, Meltzer P, Chen Y et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature 2000: 406: 536–540. This paper reports the discovery of a subset of melanomas identi- fied by gene expression analysis. A series of genes, involved in primitive tubular network, are associated with highly aggressive metastatic melanoma. Lee C, Hong B, Choi J M et al. Structural basis for inhibition of the replication licensing factor Cdt1 by geminin. Nature 2004: 430: 913–917. The regulation of replication origin firing at each cell cycle is due to a high interaction between Geminin and Cdt1. This interaction prevents the inappropriate reinitiation of replication on an already fired origin. This interaction has been modelized using crystal structure between these two proteins. Gonzalez M A, Tachibana K E, Laskey R A, Coleman N. Control of DNA replication and its potential clinical exploitation. Nat Rev Cancer 2005: 5: 135–141. This paper reviewed the fine regulation of DNA replication once per cell-cycle. The genes and proteins involved in this regulation Alain Sarasin, PhD With the teams of IGR and Leuven Hospital, UPR 2169-CNRS, Institut Gustave Roussy – PR2, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France 846