Sensitivity to 4-Hydroxyestradiol and Dna Repair Efficiency in Peripheral Blood Lymphocytes of Endometrial Cancer Patients

Abstract

Background: The development of hormone-dependent cancers, including endometrial carcinomas, in great part may be mediated by the genotoxic effects of estrogen metabolites, among which 4-hydroxyestradiol (4OHE2) is characterized by the most prominent DNA-damaging properties. It is assumed that the individual sensitivity to the 4OHE2 may determine the predisposition to endometrial cancer (EС). Aim: To analyze the sensitivity of peripheral blood lymphocytes (PBLs) of EC patients to the 4OHE2 and to evaluate the repair efficiency of 4OHE2-induced DNA damage. Materials and Methods: The study was performed on the PBLs of 53 EC patients and 20 healthy women. The level of DNA damage was measured using the comet assay and was expressed as % tail DNA. The DNA repair efficiency (%) was evaluated by determining the ratio between the amount of repaired DNA damage and the level of 4OHE2-induced damage that appeared after incubation of PBLs with 4OHE2. Results: In PBLs of EC patients, a higher level of 4OHE2-induced DNA damage (32.0 ± 2.2% tail DNA) and lower DNA repair efficiency (34.0 ± 4.5%) was observed compared to PBLs of healthy women (22.3 ± 2.3% tail DNA and 48.8 ± 4.5%, respectively). PBLs of EC patients with deep tumor invasion of myometrium were characterized by more prominent decrease of DNA repair than those with less invasive tumor (< ½ of myometrium) (20.9 ± 7.8 and 43.7 ± 6.7%, respectively). Furthermore, lower DNA repair efficiency was detected in the PBLs of EC patients with a family history of cancer compared to this parameter in patients with sporadic tumors (20.9±7.8 and 47.1 ± 5.5%, respectively). Conclusion: The PBLs of EC patients are characterized by increased sensitivity to the genotoxic effect of 4OHE2 and reduced repair efficiency regarding 4OHE2-induced DNA damage. A lower level of DNA repair is observed in EC patients with deep tumor myometrial invasion and a family history of cancer.

Assessment of HER-2/neu, с-MYC and CCNE1 gene copy number variations and protein expression in endometrial carcinomas

“…To collect a family history of patients, a special questionnaire was used, which included information about occurrence of malignancy in relatives, patients' living conditions and concomitant diseases. The criteria for assigning EC patients to a group of participants with a family history of cancer was the presence of malignant tumors of the female reproductive system and the gastrointestinal tract in first and second-degree relatives [13].…”

“…Separately, it is important to note that it is well known about the significant contribution of the hereditary factor to the development of EC [9][10][11][12][13][14]. However, to date the role of various types of genetic disorders in determining the hereditary susceptibility to EC is not fully understood [10,11].…”

Dna Damage in Tumor Cells and Peripheral Blood Lymphocytes of Endometrial Cancer Patients Assessed by the Comet Assay

“…However, today little is known about how the deregulation of genome integrity maintenance in carcinoma cells manifests at the systemic level, that is, on the structural and functional features of other cells in the body, including peripheral blood lymphocytes (PBLs). Meanwhile, in recent years, the issue of the possibility of using lymphocytes as surrogate markers (cells) that reflect the molecular genetic changes in the tumor is actively discussed [10][11][12].…”