Identification of Mutations Related to Cisplatin-Resistance and Prognosis of Patients With Lung Adenocarcinoma.

Rui Li,Xin Chen,Zhenyu Liang,Zekui Fang,Junfang Liu

doi:10.3389/fphar.2020.572627

Abstract

Background: Lung adenocarcinoma (LUAD) is the most common histologic type of non-small cell lung cancer (NSCLC; approximately 60%), and platinum-based chemotherapy is the cornerstone of the treatment for patients with LUAD. However, a considerable number of patients experience tumor recurrence after developing cisplatin (cis-diamminedichloroplatinum(II) or CDDP) resistance. Therefore, it is particularly important to screen primary CDDP-resistant LUAD patient populations, which can maximize the clinical benefits for these patients. Methods: Data for 61 LUAD cell lines were downloaded from the Genomics of Drug Sensitivity in Cancer (GDSC) database to screen for mutations related to CDDP susceptibility, and we conducted whole-exome sequencing (WES) of tumors from 45 LUAD patients from Zhujiang Hospital of Southern Medical University. Subsequently, the clinical prognostic value of these mutations was verified by using The Cancer Genome Atlas (TCGA)-LUAD cohort and our cohort (n = 45). Results: Based on drug sensitivity data for the GDSC-LUAD cell lines and survival analysis of the cohorts TCGA-LUAD and Local-LUAD, we found only one gene (GREB1) with mutations related to decreased CDDP sensitivity as well as worse overall survival (OS) and progression-free survival (PFS) [OS: log-rank p = 0.038, hazard ratio (HR; 95% confidence interval (95% CI)): 2.19 (0.73–6.55); PFS: log-rank p = 0.001; HR: 4.65, 95% CI: 1.18–18.37]. The GREB1-mutant (GREB1-MT) group had a higher frequency of gene mutations. Additionally, gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) suggested reduced accumulation of intracellular drugs in the GREB1-MT group, in addition to increased drug efflux and enhanced DNA damage repair and intracellular detoxification. Conclusion: This study found that GREB1 mutations may mediate the primary resistance and clinical prognosis of LUAD patients undergoing treatment with CDDP. Further functional analysis showed that GREB1 mutations are related to the known mechanism of CDDP resistance. These results suggest that GREB1 mutations are potential biomarkers for screening of CDDP resistance among LUAD patients.

Highlights

Lung cancer is the most common malignancy in the world (Bray et al, 2018), and Lung adenocarcinoma (LUAD) is the most common histologic type of nonsmall cell lung cancer (NSCLC) (Chalela et al, 2017)
CDDP sensitivity, mRNA expression and mutation data were available for 61 LUAD cell lines, and the relevant data were used for downstream analysis (Supplementary Table S1)
We used 10% mutation as a threshold to screen the mutations associated with CDDP sensitivity and employed the Mann-Whitney U test to compare the difference in CDDP sensitivity between mutant and wild-type cell lines

Summary

Introduction

Lung cancer is the most common malignancy in the world (Bray et al, 2018), and LUAD is the most common histologic type of NSCLC (approximately 60%) (Chalela et al, 2017). A considerable number of cases relapse after chemotherapy, resulting in a poor prognosis. It is important to screen for primary CDDP resistance in LUAD patients. Lung adenocarcinoma (LUAD) is the most common histologic type of nonsmall cell lung cancer (NSCLC; approximately 60%), and platinum-based chemotherapy is the cornerstone of the treatment for patients with LUAD. A considerable number of patients experience tumor recurrence after developing cisplatin (cisdiamminedichloroplatinum(II) or CDDP) resistance. It is important to screen primary CDDP-resistant LUAD patient populations, which can maximize the clinical benefits for these patients

Methods

Results

Discussion

Conclusion