Mismatch repair proteins MSH2, MLH1 expression and DNA damage in tumor cells of endometrial cancer patients with family history of cancer
O. Brieieva, N. Iurchenko, L. Buchynska
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine
Introduction: DNA repair deficiency may cause genetic instability that results in high sensitivity of cells to exogenous and endogenous DNA damaging agents. Mismatch repair has important role in the maintenance of genome integrity in tissues with high proliferative activity such as endometrium. Genetic and epigenetic defects of mismatch repair genes MSH2 and MLH1 induce accumulation of mutations leading to malignant transformation. Patients with family history of cancer may be characterized by inherited DNA repair deficiency therefore further studies are needed to assess DNA repair activity in these patients. Aim: To evaluate the level of DNA damage and mismatch repair activity in tumor cells of endometrial cancer patients considering family history of cancer. Methods: 20 endometrial cancer (EC) patients with the mean age 57.2 years were included in the study. Assessment of DNA damages in endometrial tumor cells was performed by DNA comet assay. The level of DNA damage was quantified as the mean percentage of DNA in the tail and the comet tail moment (TM). Mismatch repair activity was assessed by immunohistochemistry using primary monoclonal antibodies MSH2 (clone 25D12) and MLH1 (clone G168–15) (“Diagnostic BioSystems”). The mean percantage of immunopositive cells was calculated (LI, %). Results: 30% of EC patients had family history of gastrointestinal tract and female reproductive system cancers. Assessment of DNA damage in endometrial tumor cells revealed that TM equaled to 32.2±1.2 and the % DNA in comet tail — 51.7± 1.3. It was found that level of DNA damage in tumor cells of EC patients with family history of cancer was almost two times higher (TM 50.4±2.9; % DNA in comet tail 75.72±1.96) compared to sporadic EC (TM 27.3±1.2; % DNA in comet tail 45.2±1.5). Immunohistochemical study didn’t reveal significant difference of MSH2 expression in EC of patients with and without family history of cancer (LI 40.0±3.4% and 40.5±7.7%, respectively). Expression of MLH1 was higher in sporadic EC (LI 45.8±2.3%) compared to EC of patients with family history of cancer (LI 37.8±4.9%). Conclusions: Endometrial cancer cells of patients with family history of cancer are characterized by increased level of DNA damage that may be caused by low level of MLH1 protein expression indicating abnormalities of mismatch repair capacity.
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