Papadopoulou E, Anagnostopoulos K, Tripsianis G, Tentes I, Kakolyris S, Galazios G, Sivridis E, Simopoulos K, Kortsaris A
Laboratory of Biochemistry, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
Neoplasma. 2008;55(3):229-38.
The present study was conducted to clarify the predictive and prognostic significance of serum TGF-I(2)1 in breast cancer in relation to Ile655Val single nucleotide polymorphism (SNP) of human epidermal growth factor receptor-2 (HER-2). In a case-control study, 56 consecutive patients with primary breast cancer were prospectively included and evaluated. The control group consisted of 45 healthy women. Serum concentrations of TGF-I(2)1 were measured by quantitative sandwich enzyme immunoassay (ELISA). HER-2 SNP was genotyped using PCR-RFLP method. Serum levels of TGF-I(2)1 were significantly increased in breast cancer patients compared to healthy controls (p<0.001). For the evaluation of the diagnostic significance of serum TGF-I(2)1 the area under the receiver operating characteristic (ROC) curve (AUC) was 0.804, while the optimal cut-off point of 30.86 ng/ml was determined to classify breast cancer patients, which yielded sensitivity of 77%, specificity of 78% and accuracy of 77%. Significantly elevated serum TGF-I(2)1 levels were associated with advanced stages (p=0.023), positive lymph nodes (p=0.019) and postmenopausal status (p=0.031). A marginal trend towards higher TGF-I(2)1 levels was found among patients with Val-containing genotypes compared to homozygous Ile-Ile (p=0.094). In multivariate analysis lymph node metastases (p=0.009) remained the only significant independent determinant of high TGF-I(2)1 levels. With regard to prognostic significance for advanced stages (AUC, 0.704) and lymph node metastasis (AUC, 0.683), when the optimal cut-off value was set at 65.15 pg/ml, the sensitivity was 86% and 67%, the specificity was 60% and 62% and accuracy was 66% and 64%, respectively. Survival was shorter in patients with increased serum TGF-I(2)1 (36 months vs 46 months, p=0.022). Multivariate analysis demonstrated a marginal prognostic significance of serum TGF-I(2)1 for survival (p=0.072). The combination of high TGF-I(2)1 and Val-Val genotype predicts a worse prognosis than high serum TGF-I(2)1 alone. Our findings suggest that serum TGF-I(2)1 is involved in tumor malignancy and lymph node metastasis and could be used clinically as a useful tumor marker for evaluation, the extension and the outcome of the disease. They also provide clinical evidence for a significant association between HER-2 Ile655Val SNP and serum TGF-I(2)1, resulting to more aggressive phenotype of the tumor and poor prognosis.
本研究旨在阐明血清转化生长因子-β1（TGF-β1）在乳腺癌中与人类表皮生长因子受体2（HER-2）的Ile655Val单核苷酸多态性（SNP）相关的预测和预后意义。在一项病例对照研究中，前瞻性纳入并评估了56例连续的原发性乳腺癌患者。对照组由45名健康女性组成。采用定量夹心酶免疫测定法（ELISA）检测血清TGF-β1浓度。使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对HER-2 SNP进行基因分型。与健康对照组相比，乳腺癌患者血清TGF-β1水平显著升高（p<0.001）。为评估血清TGF-β1的诊断意义，受试者操作特征（ROC）曲线下面积（AUC）为0.804，同时确定30.86 ng/ml的最佳截断点用于对乳腺癌患者进行分类，其敏感性为77%，特异性为78%，准确性为77%。血清TGF-β1水平显著升高与晚期（p=0.023）、阳性淋巴结（p=0.019）和绝经后状态（p=0.031）相关。与纯合Ile-Ile基因型患者相比，含Val基因型患者的TGF-β1水平有升高的边缘趋势（p=0.094）。多变量分析显示，淋巴结转移（p=0.009）仍然是TGF-β1水平升高的唯一显著独立决定因素。关于晚期（AUC，0.704）和淋巴结转移（AUC，0.683）的预后意义，当最佳截断值设定为65.15 pg/ml时，敏感性分别为86%和67%，特异性分别为60%和62%，准确性分别为66%和64%。血清TGF-β1升高的患者生存期较短（36个月对46个月，p=0.022）。多变量分析显示血清TGF-β1对生存期有边缘性预后意义（p=0.072）。高TGF-β1与Val-Val基因型的联合预测的预后比单独高血清TGF-β1更差。我们的研究结果表明，血清TGF-β1参与肿瘤恶性进展和淋巴结转移，可在临床上用作评估疾病的扩展和转归的有用肿瘤标志物。它们还为HER-2 Ile655Val SNP与血清TGF-β1之间的显著关联提供了临床证据，导致肿瘤更具侵袭性的表型和不良预后。
