The Overall Survival of Breast Cancer Patients Depends on a Combination of Polymorphisms of Tumor Necrosis Factor Gene and HLA Haplotypes

Abstract

Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of a number of diseases, including oncological and autoimmune diseases. The –308(g/a)TNF and –238(G/A)TNF polymorphisms are included in the extended ancestral haplotypes covering the whole complex of HLA genes. We assumed that the previously found effect of these polymorphisms on the overall survival (OS) of breast cancer (BC) patients may be a consequence of cooperation with the genomic environment, namely, with the AH8.1 and B57 haplotypes associated with autoimmune conditions. The archival collection of DNA from 442 primary BC patients and 327 women from the control group with known –308(g/a)TNF and –238(G/A)TNF genotypes was used in the work. Four hundred and twelve BC patients were tested for AH8.1 and B57 markers. During the study, the association of –308a and –238A alleles of the TNF gene with haplotypes AH8.1 and B57, respectively, was confirmed. Analysis of the results of the study demonstrated that TNF gene polymorphisms do not affect the predisposition to BC disease, but significantly decrease the OS of BC patients; moreover, the final effect of the TNF gene polymorphisms on the disease prognosis depends on genomic context. At stage II of the disease, the carriers of the –308ag/–238GG genotype in the presence of marker AH8.1 alleles and the –308gg/–238GG carriers, regardless of AH8.1 markers, had a 10-year OS above 80%, while a 10-year OS was lower than 50% in the –308ag/–238GG carriers in the absence of AH8.1 markers and in the –308gg/–238AG genotype carriers (p = 0.0076). The mechanisms of action of –308(g/a)TNF and ‒238(G/A)TNF differ, and a decrease in OS in the carriers of minor –238A allele is mediated by its association with HLA-B*57, while a decrease in OS in the carriers of –308a, on the contrary, is not associated with the ancestral AH8.1 haplotype. Thus, two genetically determined BC patient groups that have an unfavorable prognosis in conditions of standard BC therapy were detected.