Xu Fengyan, Zhou Guiqin, Han Shaoli, Yuan Weiguang, Chen Shuang, Fu Zhenkun, Li Dalin, Zhang Hua, Li Dianjun, Pang Da
Department of Anatomy, Harbin Medical University, Harbin, China.
Department of Immunology, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University, Harbin, China.
PLoS One. 2014 Jul 10;9(7):e101138. doi: 10.1371/journal.pone.0101138. eCollection 2014.
The interaction of tumor necrosis factor-α (TNF-α) with its receptors: TNFRSF1A and TNFRSF1B is critical for the promotion of tumor growth, invasion and metastasis. To better understand the roles of single nucleotide polymorphisms (SNPs) in the TNF-α, TNFRSF1A and TNFRSF1B genes in the development of breast cancer, we explored the associations between SNPs in these three genes and breast cancer susceptibility in northeast Chinese Han women.
METHODOLOGY/PRINCIPAL FINDINGS: This case-control study was conducted among 1016 breast cancer patients and 806 age-matched healthy controls. Seven SNPs in the TNF-α (rs1800629, rs361525), TNFRSF1A (rs767455, rs4149577 and rs1800693) and TNFRSF1B (rs1061622 and rs1061624) genes were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In TNFRSF1B, the rs1061622 GT genotype and the G allele conferred a reduced susceptibility to breast cancer (P = 0.000662, OR = 0.706, 95% CI: 0.578-0.863; P = 0.002, OR = 0.769, 95% CI; 0.654-0.905, respectively). Moreover, the AG genotype, the AA genotype and the A allele in rs1061624 conferred an increased risk of breast cancer (P = 0.007, OR = 1.470, 95% CI:1.112-1.943; P = 0.00109, OR = 1.405 95% CI:1.145-1.724; P = 0.001, OR = 1.248 95% CI:1.092-1.426, respectively). These two SNPs also had associations with breast cancer risk under the dominant model. In haplotype analysis, the CTA (rs767455 C-rs4149577 T-rs1800693 A) haplotype in TNFRSF1A and the TA (rs1061622 T-rs1061624 A) haplotype in TNFRSF1B had higher frequencies in breast cancer patients (P = 0.00324; P = 0.000370, respectively), but the frequency of GG (rs1061622 G-rs1061624 G) haplotype in TNFRSF1B was lower in breast cancer patients (P = 0.000251). The associations of the three haplotypes remained significant after correcting for multiple testing. In addition, significant associations were also observed between TNFRSF1A polymorphisms and lymph node metastasis, P53, estrogen receptor (ER) and progesterone receptor (PR) statuses.
Our results suggest that rs1061622 and rs1061624 in TNFRSF1B may affect breast cancer risk, and SNPs in TNFRSF1A are associated with the clinical features of breast cancer.
肿瘤坏死因子-α（TNF-α）与其受体TNFRSF1A和TNFRSF1B的相互作用对于促进肿瘤生长、侵袭和转移至关重要。为了更好地理解单核苷酸多态性（SNP）在TNF-α、TNFRSF1A和TNFRSF1B基因在乳腺癌发生发展中的作用，我们探讨了这三个基因中的SNP与中国东北汉族女性乳腺癌易感性之间的关联。
方法/主要发现：本病例对照研究在1016例乳腺癌患者和806例年龄匹配的健康对照中进行。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对TNF-α（rs1800629、rs361525）、TNFRSF1A（rs767455、rs4149577和rs1800693）和TNFRSF1B（rs1061622和rs1061624）基因中的7个SNP进行基因分型。在TNFRSF1B中，rs1061622的GT基因型和G等位基因使乳腺癌易感性降低（P = 0.000662，OR = 0.706，95%CI：0.578 - 0.863；P = 0.002，OR = 0.769，95%CI：0.654 - 0.905）。此外，rs1061624中的AG基因型、AA基因型和A等位基因使乳腺癌风险增加（P = 0.007，OR = 1.470，95%CI：1.112 - 1.943；P = 0.00109，OR = 1.405，95%CI：1.145 - 1.724；P = 0.001，OR = 1.248，95%CI：1.092 - 1.426）。在显性模型下，这两个SNP也与乳腺癌风险相关。在单倍型分析中，TNFRSF1A中的CTA（rs767455 C - rs4149577 T - rs1800693 A）单倍型和TNFRSF1B中的TA（rs1061622 T - rs1061624 A）单倍型在乳腺癌患者中的频率较高（分别为P = 0.00324；P = 0.000370），但TNFRSF1B中GG（rs1061622 G - rs1061624 G）单倍型在乳腺癌患者中的频率较低（P = 0.000251）。在进行多重检验校正后，这三种单倍型的关联仍然显著。此外，还观察到TNFRSF1A多态性与淋巴结转移、P53、雌激素受体（ER）和孕激素受体（PR）状态之间存在显著关联。
我们的结果表明，TNFRSF1B中的rs1061622和rs1
