GRP78 内含子多态性可改善非小细胞肺癌的化疗预测。

An intronic polymorphism in GRP78 improves chemotherapeutic prediction in non-small cell lung cancer.

机构信息

Guangdong Province Key Laboratory of Medical Molecular Diagnosis, Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Dongguan, China; Cancer Institute, Affiliated Tumor Hospital, Guangzhou Medical University, Guangzhou, China.

Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.

出版信息

Chest. 2012 Jun;141(6):1466-1472. doi: 10.1378/chest.11-0469. Epub 2011 Sep 22.

DOI:10.1378/chest.11-0469

PMID:21940774

Abstract

BACKGROUND

Glucose-regulated protein 78 (GRP78) is involved in not only the progression of non-small cell lung cancer (NSCLC) but also chemotherapeutic effects. We hypothesized that an intronic polymorphism (rs430397G>A) in GRP78 affects survival among patients with NSCLC treated with platinum-based chemotherapy.

METHODS

Blood samples of patients with advanced NSCLC (IIIB/IV) were maintained in our specimen bank between 2001 and 2006. Genomic DNA was genotyped for rs430397. Associations between rs430397 and platinum-based treatment response, overall survival (OS), NSCLC-related survival, progression-free survival (PFS), and relapses were evaluated. GRP78 RNA and protein in NSCLC tissues were tested by real-time polymerase chain reaction and immunohistochemistry.

RESULTS

The AA genotype is significantly associated with platinum-based chemoresistance (P = .019) and NSCLC-related death (P = .022). OS, NSCLC-related survival, and PFS of the AA genotype group are decreased compared with the GG and AG genotype groups (log-rank P < .05, respectively). The AA group showed a higher prevalence of early NSCLC relapses than the AG and GG group (P = .030). In addition, the AA genotype showed a significantly increased risk for OS (hazard ratio, 1.95) and PFS (hazard ratio, 1.80) compared with the GG group. Functional analysis showed that NSCLC tissues with genotype AA have higher GRP78 RNA and protein expression compared with those carrying GG at rs430397.

CONCLUSIONS

The rs430397 AA genotype of GRP78 is associated with reduced survival and higher prevalence of early relapses in patients with advanced NSCLC treated with platinum-based chemotherapy.

摘要

背景

葡萄糖调节蛋白 78（GRP78）不仅参与非小细胞肺癌（NSCLC）的进展，还参与化疗效果。我们假设 GRP78 的内含子多态性（rs430397G>A）影响接受铂类化疗的 NSCLC 患者的生存。

方法

我们的标本库于 2001 年至 2006 年间保存了晚期 NSCLC（IIIB/IV）患者的血液样本。对 rs430397 进行基因分型。评估 rs430397 与铂类治疗反应、总生存期（OS）、NSCLC 相关生存期、无进展生存期（PFS）和复发之间的关系。通过实时聚合酶链反应和免疫组织化学检测 NSCLC 组织中的 GRP78 RNA 和蛋白质。

结果

AA 基因型与铂类化疗耐药显著相关（P =.019）和 NSCLC 相关死亡（P =.022）。与 GG 和 AG 基因型组相比，AA 基因型组的 OS、NSCLC 相关生存和 PFS 降低（log-rank P <.05，分别）。AA 组的早期 NSCLC 复发率高于 AG 和 GG 组（P =.030）。此外，与 GG 组相比，AA 基因型的 OS（危险比，1.95）和 PFS（危险比，1.80）风险显著增加。功能分析表明，与携带 GG 基因型的 NSCLC 组织相比，携带 rs430397AA 基因型的 NSCLC 组织的 GRP78 RNA 和蛋白质表达水平更高。