高LARGE1表达可能预示可切除非小细胞肺癌辅助化疗的获益情况。

High LARGE1 Expression May Predict Benefit from Adjuvant Chemotherapy in Resected Non-Small-Cell Lung Cancer.

作者信息

Liu Yu, Huang Shirui, Kuang Mengjiao, Wang Huiyan, Xie Qipeng

机构信息

Department of Cardiothoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China.

Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China.

出版信息

Pharmgenomics Pers Med. 2021 Jan 18;14:87-99. doi: 10.2147/PGPM.S271516. eCollection 2021.

DOI:10.2147/PGPM.S271516

PMID:33500650

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7822230/

Abstract

BACKGROUND

LARGE1 plays a pivotal role in glycosylation of alpha-Dystroglycan (α-DG) and is aberrantly downregulated in cell lines originating from epithelium-derived cancers including lung cancer. However, the expression of LARGE1 and its clinical significance in NSCLC are not clear.

MATERIALS AND METHODS

The data were collected from the TCGA database to investigate LARGE1 expression in stage I-III NSCLC and explore its associations with clinicopathological parameters and overall survival of patients. The prognostic role of LARGE1 was examined in subgroups according to clinical features and treatments. The results were validated in external cohorts from the NCBI GEO database. Gene Set Enrichment Analysis (GSEA) was performed to investigate the potential molecular mechanisms during LARGE1 alteration in NSCLC.

RESULTS

LARGE1 was aberrantly downregulated in NSCLC compared with adjacent tissues and normal lung tissues and in tumors with advanced stage compared with early stage. There was only a trend of association between high LARGE1 with OS in multivariate analysis. Surprisingly, high LARGE1 was significantly associated with improved OS in a subgroup of the patients with adjuvant chemotherapy (ACT) and a significant interaction between LARGE1 expression and ACT was found. Improved OS after ACT was also found in patients with high LARGE1 compared to those with low LARGE1. When combining LARGE1 expression and ACT, compared with patients with non-ACT, HR of low LARGE1/ACT was 0.592 (95% CI=0.432-0.813, =0.0012), and HR of high LARGE1/ACT was 0.124 (95% CI=0.031-0.505, =0.0036). The results were verified in two external cohorts from the GEO database. GSEA indicated that LARGE1 might downregulate cell cycle pathway to improve ACT sensitivity and subsequently the prognosis in NSCLC.

CONCLUSION

High LARGE1 can be used to identify the patients with resected stage I-III NSCLC most likely to benefit from adjuvant chemotherapy.

摘要

背景

LARGE1在α-肌营养不良蛋白聚糖（α-DG）糖基化过程中起关键作用，且在源自上皮来源癌症（包括肺癌）的细胞系中异常下调。然而，LARGE1在非小细胞肺癌（NSCLC）中的表达及其临床意义尚不清楚。

材料与方法

从TCGA数据库收集数据，以研究LARGE1在I-III期NSCLC中的表达，并探讨其与临床病理参数及患者总生存期的相关性。根据临床特征和治疗方法，在亚组中研究LARGE1的预后作用。结果在来自NCBI GEO数据库的外部队列中得到验证。进行基因集富集分析（GSEA）以研究NSCLC中LARGE1改变期间的潜在分子机制。

结果

与相邻组织和正常肺组织相比，LARGE1在NSCLC中异常下调，且与早期肿瘤相比，晚期肿瘤中LARGE1也异常下调。多因素分析中，高LARGE1与总生存期（OS）之间仅存在关联趋势。令人惊讶的是，在接受辅助化疗（ACT）的患者亚组中，高LARGE1与改善的OS显著相关，并且发现LARGE1表达与ACT之间存在显著相互作用。与低LARGE1患者相比，高LARGE1患者在ACT后OS也有所改善。当结合LARGE1表达和ACT时，与未接受ACT的患者相比，低LARGE1/ACT患者的风险比（HR）为0.592（95%置信区间[CI]=0.432-0.813，P=0.0012），高LARGE1/ACT患者的HR为0.124（95%CI=0.031-0.505，P=0.0036）。结果在来自GEO数据库的两个外部队列中得到验证。GSEA表明，LARGE1可能下调细胞周期通路，以提高ACT敏感性，进而改善NSCLC的预后。