Sonic hedgehog 和 Gli1 表达可预测胰腺腺癌切除术后的预后。

Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma.

机构信息

Saint Antoine Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.

Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Versailles, France. Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, APHP, Paris, France.

出版信息

Clin Cancer Res. 2015 Mar 1;21(5):1215-24. doi: 10.1158/1078-0432.CCR-14-0667. Epub 2014 Dec 31.

DOI:10.1158/1078-0432.CCR-14-0667

PMID:25552484

Abstract

PURPOSE

Aberrant activation of the hedgehog (Hh) pathway is implicated in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. We investigated the prognostic and predictive value of four Hh signaling proteins and of the tumor stromal density.

EXPERIMENTAL DESIGN

Using tissue microarray and immunohistochemistry, the expression of Shh, Gli1, SMO, and PTCH1 was assessed in 567 patients from three independent cohorts who underwent surgical resection for PDAC. In 82 patients, the tumor stromal index (SI) was calculated, and its association with overall survival (OS) and disease-free survival (DFS) was investigated.

RESULTS

Shh and Gli1 protein abundance were independent prognostic factors in resected PDACs; low expressors for those proteins experiencing a better OS and DFS. The combination of Shh and Gli1 levels was the most significant predictor for OS and defined 3 clinically relevant subgroups of patients with different prognosis (Gli1 and Shh low; HR set at 1 vs. 3.08 for Shh or Gli1 high vs. 5.69 for Shh and Gli1 high; P < 0.001). The two validating cohorts recapitulated the findings of the training cohort. After further stratification by lymph node status, the prognostic significance of combined Shh and Gli1 was maintained. The tumor SI was correlated with Shh levels and was significantly associated with OS (P = 0.023).

CONCLUSIONS

Shh and Gli1 are prognostic biomarkers for patients with resected PDAC.

摘要

目的

hedgehog（Hh）信号通路的异常激活与胰腺导管腺癌（PDAC）的肿瘤发生有关。我们研究了四种 Hh 信号蛋白和肿瘤基质密度的预后和预测价值。

实验设计

使用组织微阵列和免疫组织化学，在接受 PDAC 手术切除的 567 名来自三个独立队列的患者中评估了 Shh、Gli1、SMO 和 PTCH1 的表达。在 82 名患者中，计算了肿瘤基质指数（SI），并研究了其与总生存期（OS）和无病生存期（DFS）的关系。

结果

Shh 和 Gli1 蛋白丰度是可切除 PDAC 的独立预后因素；这些蛋白低表达者的 OS 和 DFS 更好。Shh 和 Gli1 水平的组合是 OS 的最显著预测因子，并定义了 3 个具有不同预后的临床相关亚组（Gli1 和 Shh 低；风险比设定为 1 与 Shh 或 Gli1 高相比为 3.08，与 Shh 和 Gli1 高相比为 5.69；P < 0.001）。两个验证队列重现了训练队列的结果。进一步按淋巴结状态分层后，联合 Shh 和 Gli1 的预后意义得以维持。肿瘤 SI 与 Shh 水平相关，与 OS 显著相关（P = 0.023）。