Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America [corrected].
PLoS One. 2012;7(7):e40157. doi: 10.1371/journal.pone.0040157. Epub 2012 Jul 6.
One-fifth of patients with seemingly 'curable' pancreatic ductal adenocarcinoma (PDA) experience an early recurrence and death, receiving no definable benefit from a major operation. Some patients with advanced stage tumors are deemed 'unresectable' by conventional staging criteria (e.g. liver metastasis), yet progress slowly. Effective biomarkers that stratify PDA based on biologic behavior are needed. To help researchers sort through the maze of biomarker data, a compendium of ∼2500 published candidate biomarkers in PDA was compiled (PLoS Med, 2009. 6(4) p. e1000046).
Building on this compendium, we constructed a survival tissue microarray (termed s-TMA) comprised of short-term (cancer-specific death <12 months, n = 58) and long-term survivors (>30 months, n = 79) who underwent resection for PDA (total, n = 137). The s-TMA functions as a biological filter to identify bona fide prognostic markers associated with survival group extremes (at least 18 months separate survival groups). Based on a stringent selection process, 13 putative PDA biomarkers were identified from the public biomarker repository. Candidates were tested against the s-TMA by immunohistochemistry to identify the best markers of tumor biology. In a multivariate model, MUC1 (odds ratio, OR = 28.95, 3+ vs. negative expression, p = 0.004) and MSLN (OR = 12.47, 3+ vs. negative expression, p = 0.01) were highly predictive of early cancer-specific death. By comparison, pathologic factors (size, lymph node metastases, resection margin status, and grade) had ORs below three, and none reached statistical significance. ROC curves were used to compare the four pathologic prognostic features (ROC area = 0.70) to three univariate molecular predictors (MUC1, MSLN, MUC2) of survival group (ROC area = 0.80, p = 0.07).
MUC1 and MSLN were superior to pathologic features and other putative biomarkers as predicting survival group. Molecular assays comparing cancers from short and long survivors are an effective strategy to screen biomarkers and prioritize candidate cancer genes for diagnostic and therapeutic studies.
有五分之一看似“可治愈”的胰腺导管腺癌（PDA）患者会早期复发和死亡，他们并没有从主要手术中获得明确的益处。一些患有晚期肿瘤的患者根据传统分期标准被认为是“不可切除的”（例如肝转移），但进展缓慢。需要有效的生物标志物来根据生物学行为对 PDA 进行分层。为了帮助研究人员梳理生物标志物数据的迷宫，我们编译了一份大约 2500 个已发表的 PDA 候选生物标志物的摘要（《公共科学图书馆·医学》，2009. 6(4)，第 e1000046 页）。
在此摘要的基础上，我们构建了一个生存组织微阵列（称为 s-TMA），其中包含短期（癌症特异性死亡<12 个月，n=58）和长期幸存者（>30 个月，n=79），他们因 PDA 接受了切除术（总计，n=137）。s-TMA 作为一种生物学过滤器，可识别与生存组极端相关的真正预后标志物（至少 18 个月的生存组分离）。基于严格的选择过程，从公共生物标志物库中鉴定出 13 种潜在的 PDA 生物标志物。通过免疫组织化学对候选物进行测试，以鉴定出最能反映肿瘤生物学的标志物。在多变量模型中，MUC1（比值比，OR=28.95，3+与阴性表达，p=0.004）和 MSLN（OR=12.47，3+与阴性表达，p=0.01）高度预测癌症特异性早期死亡。相比之下，病理因素（大小、淋巴结转移、切缘状态和分级）的比值比均低于三，且均无统计学意义。ROC 曲线用于比较四种病理预后特征（ROC 面积=0.70）与三种单变量分子预测因子（MUC1、MSLN、MUC2）对生存组的预测能力（ROC 面积=0.80，p=0.07）。
MUC1 和 MSLN 优于病理特征和其他潜在生物标志物，可预测生存组。比较短期和长期幸存者癌症的分子检测是筛选生物标志物和确定候选癌症基因进行诊断和治疗研究的有效策略。
