Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90033, USA.
Ann Surg. 2010 May;251(5):857-64. doi: 10.1097/SLA.0b013e3181c97fcf.
The aim of this study was to determine whether the risk of systemic disease after esophagectomy could be predicted by angiogenesis-related gene polymorphisms.
Systemic tumor recurrence after curative resection continues to impose a significant problem in the management of patients with localized esophageal adenocarcinoma (EA). The identification of molecular markers of prognosis will help to better define tumor stage, indicate disease progression, identify novel therapeutic targets, and monitor response to therapy. Proteinase-activated-receptor 1 (PAR-1) and epidermal growth factor (EGF) have been shown to mediate the regulation of local and early-onset angiogenesis, and in turn may impact the process of tumor growth and disease progression.
We investigated tissue samples from 239 patients with localized EA treated with surgery alone. DNA was isolated from formalin-fixed paraffin-embedded normal esophageal tissue samples and polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism and 5'-end [gamma-P] ATP-labeled polymerase chain reaction methods.
PAR-1 -506 ins/del (adjusted P value=0.011) and EGF +61 A>G (adjusted P value=0.035) showed to be adverse prognostic markers, in both univariate and multivariable analyses. In combined analysis, grouping alleles into favorable versus nonfavorable alleles, high expression variants of PAR-1 -506 ins/del (any insertion allele) and EGF +61 A>G (A/A) were associated with a higher likelihood of developing tumor recurrence (adjusted P value<0.001).
This study supports the role of functional PAR-1 and EGF polymorphisms as independent prognostic markers in localized EA and may therefore help to identify patient subgroups at high risk for tumor recurrence.
本研究旨在确定血管生成相关基因多态性是否可预测食管切除术后全身疾病的风险。
局部食管腺癌（EA）患者根治性切除术后的全身肿瘤复发仍然是治疗管理中的一个重大问题。预后分子标志物的鉴定将有助于更好地定义肿瘤分期、指示疾病进展、确定新的治疗靶点并监测治疗反应。蛋白酶激活受体 1（PAR-1）和表皮生长因子（EGF）已被证明可调节局部和早期血管生成的调节，进而可能影响肿瘤生长和疾病进展过程。
我们研究了 239 例接受单纯手术治疗的局部 EA 患者的组织样本。从福尔马林固定石蜡包埋的正常食管组织样本中分离 DNA，并使用聚合酶链反应-限制性片段长度多态性和 5'-端[γ-P]ATP 标记聚合酶链反应方法分析多态性。
PAR-1-506ins/del（调整后的 P 值=0.011）和 EGF+61A>G（调整后的 P 值=0.035）在单变量和多变量分析中均显示为不良预后标志物。在联合分析中，将等位基因分为有利和不利等位基因，PAR-1-506ins/del（任何插入等位基因）和 EGF+61A>G（A/A）的高表达变体与发生肿瘤复发的可能性更高相关（调整后的 P 值<0.001）。
本研究支持功能性 PAR-1 和 EGF 多态性作为局部 EA 独立预后标志物的作用，因此可能有助于识别肿瘤复发风险较高的患者亚组。
