RS4673 and pon1 level in blood plasma – new prospects in prediction and early diagnostics of anthracycline-mediated cardiotoxicity

Abstract

The purpose of this study was to research the effectiveness of molecular genetic tests based on the determination of the rs4673 CYBA polymorphism (c.242C>T) and the level of paraoxonase 1 (PON1) in the blood plasma of patients with breast cancer (BC) for predicting and diagnosing anthracycline-mediated cardiotoxicity (AMC). The genotyping of rs4673 CYBA (c.242C>T) and the study of the PON1 level in the blood plasma of 280 patients of the Caucasian type with a histologically verified diagnosis of breast cancer, who received complex treatment on the basis of the National Medical Research Center of Oncology, were carried out. Based on the results of observation for at least 8 months, two groups were identified: group 1 (257 people) without diagnosed cardiovascular changes; group 2 (23 people) - patients with subacute and early chronic AMC. It was found that carriers of the rs4673 polymorphism increase the likelihood of developing AMC by 6.8 times (p = 0.001). In the blood plasma of both groups of patients, an increase in the level of PON1 was described after the fourth course compared to the initial level (group 1 - p = 0.036, group 2 - p = 0.048). The level of the studied enzyme was higher in the blood plasma of patients with diagnosed AMC compared with patients without cardiovascular complications (before chemotherapy - p = 0.001, after the fourth course - p = 0.023). The test based on the measurement of the concentration of PON1 in the blood plasma of patients after the fourth course of chemotherapy was distinguished by high quality metrics: sensitivity - 100%, specificity - 70.8%, area under the ROC-curve (AUC) - 0.825 with a threshold level of PON1 equal to 2, 9 ng/μL. The presence of the T/T genotype caused a high level of PON1 in the blood plasma after the fourth course of chemotherapy (p = 0.012). The results of our work are of undoubted practical importance, since they allow us to obtain data on the prognosis and diagnosis of a patient in a short time, which can later be verified using clinical and instrumental methods.

Genetic polymorphisms associated with the development of arrhythmic type of cardiovascular events

“…Существует ряд работ, в которых был проведен анализ небольшого количества полиморфизмов, достоверно ассоциированных с развитием кардиотоксичности, у пациентов, получающих терапию, в схему которой входили антрациклиновые соединения. Случаи антрациклининдуцированной кардиотоксичности, сочетанной с набором определенных полиморфизмов в генах АВСС2, HIF1A, CDKN2A/В и др., дает возможность предположить, что не только наличие общепринятых факторов влияет на вероятность возникновения кардиотоксических осложнений [11]. В настоящее время уже описана подгруппа мутационных изменений генов, которые участвуют в транспорте лекарственных препаратов и достоверно вызывают эндотелиои кардиотоксичность у пациентов, находящиеся на противоопухолевой терапии [12].…”