Papadopoulou E, Tripsianis G, Anagnostopoulos K, 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(2):113-21.
HER-2 (human epidermal growth factor receptor-2) proto-oncogene is a member of the EGFR family and plays an important role in the regulation of cell growth, differentiation and survival and is involved in the regulation of normal breast growth and development. Alterations of HER-2 have been associated with carcinogenesis and poor prognosis of breast cancer. The present case-control study was conducted to clarify the predictive and prognostic significance of serum HER-2 protein in breast cancer patients in relation to Ile655Val single nucleotide polymorphism (SNP) of this gene. Fifty-six consecutive patients with primary breast cancer and 45 healthy women were prospectively included and evaluated. Serum levels of HER-2 were significantly increased in breast cancer patients compared to healthy controls (p=0.035). The optimal cut-off point of 1.98 ng/ml, which was determined to classify breast cancer patients, yielded sensitivity of 54%, specificity of 73% and accuracy of 62%. Significantly elevated serum HER-2 levels were associated with lymphovascular invasion (p=0.022), poor differentiation (p=0.011), advanced clinical stages (p=0.001), lymph node metastasis (p=0.011), higher number of positive lymph nodes (p=0.007) and the immunohistochemical overexpression of HER-2 protein (p=0.016). Regarding to HER-2 Ile655Val SNP, Ile-Val and Val-Val genotypes exhibited highly significant serum HER-2 elevation compared to homozygous Ile-Ile (both p<0.001). In multivariate analysis advanced stages (p=0.003) and Val-containing genotypes (p=0.009) remained the two significant independent determinants of high HER-2 levels. Survival analysis demonstrated an independent prognostic significance of homozygous Val-Val genotype for reduced survival (p=0.045), but not of serum HER-2 (p=0.181). Our findings confirm that serum HER-2 could be used clinically as a useful tumor marker for the diagnosis and the progression of breast cancer. Furthermore, they provide clinical evidence that HER-2 Ile655Val SNP does affect serum HER-2 levels and it can be regarded as a predictive biomarker for breast cancer patients with poor prognosis.
HER-2（人表皮生长因子受体2）原癌基因是表皮生长因子受体（EGFR）家族的成员之一，在细胞生长、分化及存活的调控中发挥重要作用，参与正常乳腺的生长和发育过程。HER-2的改变与乳腺癌的发生及不良预后相关。本病例对照研究旨在阐明血清HER-2蛋白在乳腺癌患者中相对于该基因Ile655Val单核苷酸多态性（SNP）的预测及预后意义。前瞻性纳入并评估了56例连续性原发性乳腺癌患者和45名健康女性。与健康对照相比，乳腺癌患者血清HER-2水平显著升高（p = 0.035）。确定用于乳腺癌患者分类的最佳截断点为1.98 ng/ml，其敏感性为54%，特异性为73%，准确性为62%。血清HER-2水平显著升高与淋巴管浸润（p = 0.022）、低分化（p = 0.011）、临床晚期（p = 0.001）、淋巴结转移（p = 0.011）、阳性淋巴结数量较多（p = 0.007）及HER-2蛋白免疫组化过表达（p = 0.016）相关。关于HER-2 Ile655Val SNP，与纯合Ile-Ile基因型相比，Ile-Val和Val-Val基因型血清HER-2水平显著升高（p均<0.001）。多因素分析显示，晚期（p = 0.003）和含Val基因型（p = 0.009）仍然是HER-2高水平的两个显著独立决定因素。生存分析表明，纯合Val-Val基因型对生存降低具有独立的预后意义（p = 0.045），而血清HER-2水平则无此意义（p = 0.181）。我们的研究结果证实，血清HER-2可在临床上用作诊断和监测乳腺癌进展的有用肿瘤标志物。此外，研究结果提供了临床证据，表明HER-2 Ile655Val SNP确实影响血清HER-2水平，可被视为预后不良乳腺癌患者的预测生物标志物。
