Perspective

DNA and tissue microarrays have rapidly increased the molecular information on melanoma development and progression. However, there are several challenges left when different arrays are estimated in a clinical point of view. Why are the same markers measured in IHC and serum analysis assays only rarely upregulated in gene array-based analysis? There can be several explanations. The expression levels of studied ''traditional'' markers are usually estimated between different patients, thus there is always an artificial cut-off point, which is often more researcher-dependent than related to negative and positive controls. It is also evident that even if a gene is upregulated in an array analysis, it does not necessarily mean that there is an increase in the function of the protein which it codes. Comparison of results gained from distinct DNA microarray studies has brought specificity into array analyses. The function of a desired gene can be studied by RNA interference (RNAi) method, by specific gene knockdowns in mammalian cells. RNA interference analysis shows the biological effect of a specific inhibition of gene expression and thus suggests its therapeutic significance. However, there is no consensus at the moment on how to translate these microarray profiles into clinical utility.

Heterogeneity of gained gene profiles between different studies is a problem. Although several melanoma-''specific'' array results have been published there is still no melanoma-specific repeatable gene profile available. In in vitro studies with cultured cell lines this can be partly explained by the heterogeneity of cellular subpopulations of the same pathological origin. However, clustering analyses also only rarely end up in a similar gene expression profile despite the fact that patients' clinical features between different studies have been quite homogeneous. Reliability of clustering results and profiles has been studied widely, and there are also possibilities of statistical errors. Pusztai et al.[32] have pointed out the importance of array standardization. Arrays can contain cDNAs of variable lengths or small oligonucleotide sequences leading to differences in signal intensity.[32] There is also variability in the control tissue and sampling method used. Symmans et al.[33] have clearly demonstrated that transcriptional profiles from the same tumor differ according to sampling method, i.e., fine needle aspiration and core needle biopsy yield different gene expression profiles.

There are also some ethical problems. Not all patients want to know their gene expression profile, although it would be worth assessing because of increased clinical risk factors. Similarly, it is not perfectly certain that gene profiles do not change during melanoma progression, and it is not always safe or even ethical to take serial biopsies during disease progression only to detect gene profiles. Detection of gene profile has been shown to have a survival value in breast cancer,[20] but, so far, there is no evidence supporting gene or tissue arrays or proteomics as a source of any information, which would increase the survival of melanoma patients. Furthermore, Ntzani and Ioannidis[34] have shown in their analysis that only a limited number of the DNA microarray studies performed to address cancer outcome actually had prognostic value.

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