Abstract

Tumor necrosis factor (TNF) plays an important role in the pathogenesis of breast cancer (BC). The -308(G/A)TNF polymorphism allele -308A is part of the autoimmune ancestral haplotype AH8.1 associated with elevated serum sTNF levels. Previously, we showed a decrease in overall survival for carriers -308A/AH8.1-. The aim of the study was to assess the effect of haplotypes AH8.1 on the level of sTNF and clinical and morphological characteristics of BC patients. The study included 100 people with adjuvant radiotherapy treatment. The concentration of sTNF was determined by the ELISA. Additionally, 30 archival DNA samples of primary BC patients carrying the allele -308A with a known sTNF level were genotyped. 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. Based on the polymorphism of -308(G/A)TNF and marker alleles of haplotype AH8.1, three comparison groups were identified: -308GG carriers of the TNF gene independently of haplotype AH8.1 (76%), which were used as a control; -308A/AH8.1- carriers (9%); and -308A/M(AH8.1)+ carriers of at least one haplotype AH8.1 allele (15%). The comparison groups had no statistically significant differences regarding the stage of the disease, the degree of malignancy, the histological type, and the receptor status of the tumor. The level of sTNF was significantly higher in the genetic group -308A/AH8.1– both before surgery and before and after adjuvant radiotherapy. In BC patient carriers of the TNF gene allele -308A, the autoimmune haplotype AH8.1 has a normalizing effect on the production of sTNF to a level comparable to the level of cytokine in the group of carriers of the common -308GG genotype. The genetic group -308A/AH8.1– with an increased level of sTNF has been identified, for which, bearing in mind its prognostic unfavorability, anti-TNF therapy can presumably be offered. The results obtained can be used in the framework of personalized medicine.

中文翻译：

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自身免疫单倍型 AH8.1 使乳腺癌患者血清中的肿瘤坏死因子水平正常化

摘要

肿瘤坏死因子 (TNF) 在乳腺癌 (BC) 的发病机制中起重要作用。- 308(G/A)TNF多态性等位基因 - 308A是与血清 sTNF 水平升高相关的自身免疫性祖先单倍型AH8.1的一部分。以前，我们显示携带者 - 308A/AH8.1 -的总体存活率下降。该研究的目的是评估单倍型AH8.1对 BC 患者的 sTNF 水平以及临床和形态学特征的影响。该研究包括 100 名接受辅助放疗治疗的人。sTNF 的浓度通过 ELISA 测定。此外，携带等位基因 - 308A的原发性 BC 患者的 30 个存档 DNA 样本对已知 sTNF 水平的患者进行基因分型。等位基因 - 308(G/A)TNF和单倍型AH8.1的标记等位基因（HLA-A*01、HLA-B*08和HLA-DRB1*03）通过等位基因特异性 PCR 确定。基于 - 308(G/A)TNF的多态性和单倍型 AH8.1 的标记等位基因，确定了三个比较组：一个控件；- 308A/AH8.1-运营商 (9%)；- 308A/M(AH8.1)+至少一种单倍型AH8.1的携带者等位基因 (15%)。对照组在疾病分期、恶性程度、组织学类型和肿瘤受体状态方面无统计学差异。sTNF 水平在遗传组 - 308A/AH8.1 -手术前和辅助放疗前后均显着升高。在TNF基因等位基因 - 308A的 BC 患者携带者中，自身免疫单倍型AH8.1对 sTNF 的产生具有正常化作用，其水平与常见 - 308GG基因型携带者组中的细胞因子水平相当。基因组——308A/AH8.1– 已确定 sTNF 水平升高，考虑到其预后不利，可能会提供抗 TNF 治疗。获得的结果可用于个性化医疗的框架。