Bachmann Hagen S, Otterbach Friedrich, Callies Rainer, Nückel Holger, Bau Maja, Schmid Kurt W, Siffert Winfried, Kimmig Rainer
Institute of Pharmacogenetics, University of Duisburg-Essen, Germany.
Clin Cancer Res. 2007 Oct 1;13(19):5790-7. doi: 10.1158/1078-0432.CCR-06-2673.
Expression of the antiapoptotic and antiproliferative protein Bcl-2 has been repeatedly shown to be associated with better clinical outcome in breast cancer. We recently showed a novel regulatory (-938C>A) single-nucleotide polymorphism (SNP) in the inhibitory P2 BCL2 gene promoter generating significantly different BCL2 promoter activities.
Paraffin-embedded neoplastic and nonneoplastic tissues from 274 patients (161 still alive after a follow-up period of at least 80 months) with primary unilateral invasive breast carcinoma were investigated. Bcl-2 expression of tumor cells was shown by immunohistochemistry; nonneoplastic tissues were used for genotyping. Both the Bcl-2 expression and the (-938C>A) genotypes were correlated with the patients' survival.
Kaplan-Meier curves revealed a significant association of the AA genotype with increased survival (P = 0.030) in lymph node-negative breast cancer patients, whereas no genotype effect could be observed in lymph node-positive cases. Ten-year survival rates were 88.6% for the AA genotype, 78.4% for the AC genotype, and 65.8% for the CC genotype. Multivariable Cox regression identified the BCL2 (-938CC) genotype as an independent prognostic factor for cancer-related death in lymph node-negative breast carcinoma patients (hazard ratio, 3.59; P = 0.032). Immunohistochemical Bcl-2 expression was significantly associated with the clinical outcome of lymph node-positive but not of lymph node-negative breast cancer patients. In lymph node-negative cases, the (-938C>A) SNP was both significantly related with the immunohistochemically determined level of Bcl-2 expression (P = 0.044) and the survival of patients with Bcl-2-expressing carcinomas (P = 0.006).
These results suggest the (-938C>A) polymorphism as a survival prognosticator as well as indicator of a high-risk group within patients with lymph node-negative breast cancer.
抗凋亡和抗增殖蛋白Bcl-2的表达反复显示与乳腺癌更好的临床结局相关。我们最近在抑制性P2 BCL2基因启动子中发现了一种新型调控性（-938C>A）单核苷酸多态性（SNP），其产生显著不同的BCL2启动子活性。
对274例原发性单侧浸润性乳腺癌患者（161例在至少80个月的随访期后仍存活）的石蜡包埋肿瘤组织和非肿瘤组织进行研究。通过免疫组织化学显示肿瘤细胞的Bcl-2表达；非肿瘤组织用于基因分型。Bcl-2表达和（-938C>A）基因型均与患者生存相关。
Kaplan-Meier曲线显示，AA基因型与淋巴结阴性乳腺癌患者生存率增加显著相关（P = 0.030），而在淋巴结阳性病例中未观察到基因型效应。AA基因型的10年生存率为88.6%，AC基因型为78.4%，CC基因型为65.8%。多变量Cox回归确定BCL2（-938CC）基因型是淋巴结阴性乳腺癌患者癌症相关死亡的独立预后因素（风险比，3.59；P = 0.032）。免疫组织化学Bcl-2表达与淋巴结阳性而非淋巴结阴性乳腺癌患者的临床结局显著相关。在淋巴结阴性病例中，（-938C>A）SNP与免疫组织化学测定的Bcl-2表达水平（P = 0.044）以及Bcl-2表达癌患者的生存（P = 0.006）均显著相关。
这些结果表明（-938C>A）多态性可作为淋巴结阴性乳腺癌患者的生存预后指标以及高危组指标。
