RESUMO
Endometrial cancer is the most prevalent gynecologic malignancy with a high risk of recurrence. Local recurrence occurs in 7-20% of patients with treated stage I cancer within 3 years after primary treatment. In this study, we found significantly elevated mRNA expression levels of the oncoprotein KRAS, along with two replicative stress markers, ATR and CHEK1, in samples of endometrial carcinomas of endometrium (ECE) from patients with relapse. In contrast, mRNA expression levels of the studied genes were low and uniform in samples from patients without relapse. Elevated levels of KRAS protein and the phosphorylated form of ATR/CHEK1 were distinguishing features of recurrent ECE. A strong positive correlation was found between elevated mRNA and protein levels of the studied molecules. Elevated KRAS protein levels are characteristic of poorly differentiated (G3) endometrial carcinomas with deep myometrial invasion in patients without recurrence. In contrast, in patients with recurrence, higher protein levels of KRAS, pATR and pCHEK1 were observed in samples of G1-2 endometrial carcinomas, with statistically significant differences confirmed for pATR. High pCHEK1 protein levels are associated with deep tumor invasion in the myometrium among patients with recurrence. ROC analysis confirmed that evaluating the specificity and sensitivity of KRAS, pATR and pCHEK1 predicts recurrence development in patients with ECE. Our findings indicate that markers of replicative stress may play a significant role in ECE pathogenesis. Determining their levels in tumor samples after primary treatment could help define patients at high risk of recurrence and guide consequent courses of treatment.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Quinase 1 do Ponto de Checagem , Neoplasias do Endométrio , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Feminino , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Pessoa de Meia-Idade , Quinase 1 do Ponto de Checagem/metabolismo , Quinase 1 do Ponto de Checagem/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/metabolismo , Fatores de Risco , Idoso , Proteínas ras/genética , Proteínas ras/metabolismo , Regulação Neoplásica da Expressão Gênica , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismoRESUMO
BACKGROUND: Individual susceptibility to endogenous and/or exogenous DNA damage depends on DNA repair efficiency and can be evaluated using the comet assay with bleomycin as genotoxic agent. The aim of the study was to evaluate baseline and bleomycin-induced DNA damage and DNA repair capacity in peripheral blood lymphocytes (PBLs) of endometrial cancer (EC) patients considering a family history of cancer. METHODS: DNA damage was analyzed in PBLs of 45 EC patients compared to a control group of 10 healthy women, using the comet assay. The level of DNA damage was determined by the% tail DNA. RESULTS: The level of baseline DNA damage in PBLs of EC patients was significantly higher (% DNA in tail 9.31 ± 15.32) than in healthy women (% DNA in tail 3.41 ± 4.71) (P <0.01). PBLs of EC patients repaired less bleomycin-induced DNA damage (removed% DNA in tail 63.94 ± 20.92) than PBLs of healthy individuals (removed% DNA in tail 80.24 ± 3.03) (P <0.001). Efficiency of DNA repair in PBLs of EC patients depended on the family history of cancer. The amount of restored damaged DNA was significantly lower (removed% DNA in tail 36.24 ± 14.05%) in EC patients with a family history of cancer compared to patients with sporadic EC (removed% DNA in tail 64.91 ± 19.36%) (P <0.004). CONCLUSIONS: Lymphocytes of EC patients are characterized by an increased basal level of DNA damage as well as deficiency in DNA repair. DNA repair is less efficient in PBLs of EC patients with a family history of cancer compared to patients with sporadic cancer.