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.

中文翻译：

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乳腺癌患者的总生存期取决于肿瘤坏死因子基因多态性和 HLA 单倍型的组合

摘要 肿瘤坏死因子 (TNF) 是一种促炎细胞因子，参与多种疾病的发病机制，包括肿瘤和自身免疫疾病。–308(g/a)TNF 和 –238(G/A)TNF 多态性包含在覆盖整个 HLA 基因复合体的扩展祖先单倍型中。我们假设之前发现的这些多态性对乳腺癌 (BC) 患者总生存 (OS) 的影响可能是与基因组环境合作的结果，即与自身免疫病相关的 AH8.1 和 B57 单倍型。在这项工作中使用了来自 442 名原发性 BC 患者和来自对照组的 327 名女性的 DNA 档案收集，这些女性具有已知的 –308(g/a)TNF 和 –238(G/A)TNF 基因型。测试了 412 名 BC 患者的 AH8.1 和 B57 标志物。在学习期间，TNF 基因的–308a 和–238A 等位基因分别与单倍型AH8.1 和B57 的关联得到证实。研究结果分析表明，TNF基因多态性不影响BC疾病的易感性，但显着降低BC患者的OS；此外，TNF基因多态性对疾病预后的最终影响取决于基因组背景。在疾病的 II 期，存在标记 AH8.1 等位基因的 –308ag/–238GG 基因型携带者和 –308gg/–238GG 携带者（无论 AH8.1 标记如何）的 10 年 OS 高于 80 %，而在没有 AH8.1 标记的情况下，–308ag/–238GG 携带者和 –308gg/–238AG 基因型携带者的 10 年 OS 低于 50% (p = 0.0076)。–308(g/a)TNF和–238(G/A)TNF的作用机制不同，次要 –238A 等位基因携带者的 OS 下降是由其与 HLA-B*57 的关联介导的，而 –308a 携带者的 OS 下降，相反，与祖先 AH8.1 无关单倍型。因此，检测到在标准 BC 治疗条件下具有不利预后的两个基因决定的 BC 患者组。