Expression of mismatch repair enzymes, hMLH1 and hMSH2 is not associated with microsatellite instability and P53 protein accumulation in basal cell carcinoma

Abstract

Microsatellite instability (MSI) constitutes an alternative-to the chromosomal instability-pathway of carcinogenesis for certain tumour types with prognostic and therapeutic significance for the respective patients. MSI is caused by mutations in mismatch repair (MMR) genes, mainly hMLH1, hMSH2, leading to a defective MMR system. The role of MSI in basal cell carcinoma (BCC) has not been clearly delineated yet. p53 gene as a target for ultraviolet radiation-induced mutations may enhance genomic instability in BCC, with loss of its function. Our aim was to investigate the involvement of MSI and expression of hMLH1 and hMSH2 in parallel with P53 protein accumulation in the pathogenesis of BCC and its possible correlation to the clinicopathological features of the patients. The presence of MSI was investigated in 76 BCCs using mononucleotide microsatellite markers, BAT-25, BAT-26 and TGF-beta receptor type II (TGF-beta-RII). Additionally, 3 dinucleotide markers were analysed in 20 cases in which matched normal tissue was available. The expression of hMLH1, hMSH2 and P53 proteins was evaluated by immunohistochemical analysis. Alterations of the BAT-26 marker were observed in one fibroepithelioma of Pincus, one nodular and one multifocal superficial BCC. A keratotic BCC showed an altered BAT-25 locus. Two samples, a multifocal superficial and a nodular BCC, displayed MSI at two markers (BAT-25 and BAT-26; and BAT-25 and TGF-beta-RII, respectively). Three more cases, a metatypical, a multifocal superficial and a signet ring BCC exhibited frameshift mutations in the TGF-beta-RII. No sample showed length alterations at the dinucleotide markers examined. hMLH1 and hMSH2 protein immunohistochemical expression was scored positive in 46 and 49 out of 52 cases respectively. P53 accumulation was observed in 27 out of 56 samples. Correlation of the molecular and immunohistochemical findings with the clinicopathological parameters produced no statistically significant results. No correlation between MSI and hMLH1, hMSH2 or P53 protein expression was determined. MSI appears to play a minor role in the pathogenesis of BCCs being present only in a small subset of such tumours.

B-Raf Mutations, Microsatellite Instability and p53 Protein Expression in Sporadic Basal Cell Carcinomas

“…Genomic DNA Isolation DNA extraction was performed by standard protocols of Proteinase K digestion followed by phenol/chloroform extraction as previously described [11].…”

“…Immunohistochemistry assessment was performed as previously described [11]. Immunostaining was evaluated after light microscope evaluation in at least 10 high power fields throughout the tumour area.…”

Evidence that dysregulated DNA mismatch repair characterizes human nonmelanoma skin cancer

“…found that one of 47 BCCs and two of 49 SCCs exhibited MSI 25 and, similarly, Saetta et al. found that nine of 76 BCCs exhibited MSI 26 . Kushida et al.…”

Correlation between cell cycle proteins and hMSH2 in actinic cheilitis and lip cancer

“…Both lesions have similar characteristics with skin lesions and also share the same main etiological agent, ultraviolet (UV) radiation, particularly the UVB [33]. The carcinogenesis process induced by UV, is still not fully elucidated, but it is known that exposure to endogenous and exogenous genotoxic agents, such as UV, can lead to oncogenic mutations resulting from perturbation of the cell cycle and damage to DNA repair systems [15,30,31].…”

“…The relationship between MMR genes and function of the p53 tumor suppressor gene has been of interest since that p53 is essential in the protection of cell DNA damage induced by UVB radiation, by promoting cell cycle arrest or apoptosis of damaged cells [1,12,31,37]. Activation of p53 induces the expression of several genes, including cyclindependent kinase inhibitor p21 WAF1/CIP1 gene (p21) [18,19].…”