Microsatellite instability secondary to replication errors (RER), characterized by length changes at repetitive loci scattered throughout the genome, is a recently recognized genetic mechanism important in the development of some human cancers. Although RER has been reported in sebaceous gland tumors from patients with the Muir-Torre syndrome, the frequency of RER in human non-melanoma and melanoma skin cancers is not known. In this study, we investigated the importance of RER in human skin carcinogenesis. RER was identified in three of four actinic keratoses from a patient belonging to a kindred with documented Muir-Torre syndrome, which indicates that defective DNA replication may contribute to skin cancer development in such patients. Examination of a series of tumors from patients without Muir-Torre, including 137 skin cancers (47 basal cell carcinomas, 49 squamous cell carcinomas, and 41 primary malignant melanomas), 19 actinic keratoses, and 20 cases of Bowen's disease, using 10 or more microsatellite markers, identified repeat-sequence instability in less than 5% of the tumors studied. In six of the eight tumors, the sole change was an alteration 2 base pairs in length at a single locus. One patient with a squamous cell carcinoma showed changes at multiple loci suggesting defective mismatch repair. Although the low frequency of RER found in this study of a large series of human skin tumors suggests that this phenomenon is uncommon in patients with skin cancer, the identification of RER at multiple loci in two patients suggests that error-prone replication may be important in skin cancer development in some individuals.
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"These results contrasted to those found in immunocompetent patients where AMLs and (non-Muir-Torre related) SGCs are microsatellite stable (Rimsza et al., 2000; Harwood et al., 2001). As less than 5% of the cutaneous SCCs and BCCs in immunocompetent patients display MSI (Quinn et al., 1995; Gray et al., 2006; Saetta et al., 2007), we hypothesized that cutaneous skin carcinomas of this specific group of patients might display MSI as a result of the azathioprine treatment. This could also be a possible explanation for the higher incidence of SCCs observed in azathioprine-using OTRs compared to OTRs on other drugs (Ulrich and Stockfleth , 2007; Crespo-Leiro et al., 2008). "
"Malignant skin tumors including malignant melanoma are frequently characterized by an increased incidence of mutations in microsatellite repeat sequences (Quinn et al., 1995). Microsatellite instability is a genetic mechanism important in the development of various human cancers that is characterized by length changes at repetitive loci scattered throughout the genome (Charames and Bapat, 2003). "
[Show abstract][Hide abstract] ABSTRACT: The mechanisms by which the post-replicative DNA mismatch repair (MMR) enzyme MSH2 is involved in the complex response mechanisms to UV damage are yet to be clarified. Here, we show increased levels of MSH2 mRNA in malignant melanoma, metastases of melanoma, and melanoma cell (MeWo) lines as compared with melanocytic nevi or primary cultured benign melanocytes. UV-B treatment modulated MSH2 expression and silencing of MSH2 gene expression using small interfering RNA technology regulated UV-B-induced cell cycle arrest and apoptosis in human MeWo. We show that MSH2-deficient non-malignant mouse fibroblasts (MEF-/-) are partially resistant against UV-B-induced apoptosis and show reduced S-Phase accumulation. In addition, we show that an Msh2 point mutation (MEFGA) that affects MMR does not affect UV-B-induced apoptosis. In conclusion, we demonstrate that MSH2 modulates in human melanocytes both UV-B-induced cell cycle regulation and apoptosis, most likely via independent, uncoupled mechanisms.
Full-text · Article · Feb 2008 · Journal of Investigative Dermatology
"The biological defect causing the low MSI (MSI-L) phenotype, on the other hand, is not so well understood. Early reports established that the frequency of MSI in primary melanoma ranges from 2 to 20% (Peris et al., 1995; Quinn et al., 1995; Tomlinson et al., 1996). Subsequent studies have suggested that the frequency of MSI in melanoma increases during the metastatic process, up to 38% in a group of regional and distant metastases (Palmieri et al., 2000) and 77% in lymph node metastases (Richetta et al., 2001). "
[Show abstract][Hide abstract] ABSTRACT: Tumor spread to distant organs is the most serious consequence of melanoma, as only 10-20% of stage IV patients respond to current chemotherapies. Tumor sensitivity to alkylating agents is affected by the activity of cellular DNA repair proteins, such as O(6)-methylguanine DNA methyltransferase (MGMT) and the DNA mismatch repair proteins. Chemosensitivity may be enhanced by reduced MGMT activity, but the frequency of MGMT promoter silencing through hypermethylation is unknown in distant melanoma metastases. The frequency and significance of microsatellite instability (MSI) in metastatic melanoma is also unclear, and it has been suggested that MSI frequency increases during the metastatic process. We undertook an analysis of 84 melanoma metastases from 47 patients. MGMT methylation was detected using methylation-specific PCR in 26 of the 84 metastases (31%), but there was discordance between individual metastases from the same patient. Therefore, as a result of this variation, MGMT methylation may have only limited value as a predictor of chemosensitivity. High MSI involving mononucleotide repeat markers was not found. Low MSI was detected in five of 50 metastases (10%) and only one of the five metastases also had MGMT methylation. These results demonstrate that in contrast to some previous reports, these tumors have a low frequency of MSI.
Full-text · Article · Feb 2006 · Journal of Investigative Dermatology