Features of the Systemic Response to Adjuvant Radiation Therapy in Carriers of Polymorphism -308(G/A)TNF in Breast Cancer Patients

Abstract

Background: Adjuvant radiation therapy (ART), an integral part of locoregional breast cance (BC) therapy, acting not only locally, but also systemically and leads to a shift in homeostasis, which is reflected in routine general clinical tests. Tumor necrosis factor (TNF) is a proinflammatory cytokine, the production of which can be influenced by the single-nucleotide substitution -308(G/A)TNF. The minor allele -308A can be included in the stable inherited haplotype AH8.1 of the HLA gene complex. At the same time, the carriage of the -308A without the AH8.1 haplotype is associated with a poor prognosis in patients with BC. The aim of the study was to evaluate the features of the systemic response to the course of ART in carriers of TNF-associated genotypes with BC. Material and methods: The sample is represented by 147 BC patients who underwent a course of ART (2 Gy in 25 fractions). Clinical and morphological characteristics and data of general clinical blood analysis were obtained from medical histories. Venous blood samples for the study were obtained at the beginning and at the end of the ART course. Alleles -308(G/A)TNF and marker alleles of haplotype AH8.1 (HLA-A×01, HLA-B×08 and HLA-DRB1×03) were determined by allele-specific PCR. sTNF concentrations were determined by the ELISA in 102 blood plasma samples. Results: TNF-associated comparison groups were identified based on genotyping: (1) 114 carriers -308GG of the TNF gene, regardless of the AH8.1 haplotype (77,6 %); (2) 23 carrier -308A(AH8.1pos) had at least one AH8.1 marker allele (15.6 %); (3) 10 carriers -308A(AH8.1neg) did not have any AH8.1 marker allele (6.8 %). In the -308A(AH8.1neg) group the average concentration of sTNF both at the beginning and at the end of ART was significantly higher and, unlike other comparison groups, did not significantly decrease at the end of the ART course. A significant decrease in absolute values was revealed during ART in a number of cases for leukocytes, platelets and lymphocytes, however within the reference values. In the group -308A(AH8.1neg) correlation analysis revealed a high strength of positive connections between sTNF and leukocytes (r=0.71; p=0.027), platelets (r=0.67; p=0.04), neutrophils (r=0.70; p=0.027) only at the end of ART, whereas at the beginning ART these correlations were weak (r≤0.3) and statistically unreliable. For other genetic groups, the revealed correlations were not strong enough. Conclusion: The revealed features of the systemic response to ART for carriers of a prognostically unfavorable genotype -308A(AH8.1neg) – a high concentration of sTNF and a positive correlation with the content of leukocytes (probably due to neutrophils) and platelets – can be considered as targets of individualized therapy.