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    KEAP1/NRF2在各组织学亚型肺癌中的变异特征比较及预后意义分析

    Comparative Analysis of Variation Characteristics and Prognostic Significance of KEAP1/NRF2 in Various Histological Subtypes of Lung Cancer

      摘要
    • 摘要:
      背景 KEAP1与NRF2（NFE2L2）是细胞内重要的抗氧化应激相关基因。这两个基因突变增强了抗氧化能力而促进癌症发生发展，但其在不同组织学类型肺癌中是否存在差异尚不清楚。
      方法 本研究在肺腺癌（lung adenocarcinoma，LUAD）、肺鳞癌（lung squamous cell carcinoma，LUSC）及大细胞神经内分泌癌（large cell neuroendocrine carcinoma，LCNEC）队列测序结果的基础上，结合cBioPortal数据库中肿瘤基因组图谱（The Cancer Genome Atlas，TCGA）研究队列相关突变以及预后数据，对LUAD、LUSC、LCNEC和小细胞肺癌（small cell lung cancer，SCLC）中KEAP1/NRF2突变频率、突变类型、发生区域以及生存预后差异进行了比较。
      结果 东西方患者KEAP1/NRF2突变率在不同组织学肺癌中分布略有差异。在我国LUSC和LCNEC中KEAP1/NRF2突变频率较高（16.81%/13.27%；16.39%/3.28%），高于LUAD（7.03%/0.0%）。在LUAD患者中，我国患者KEAP1/NRF2基因突变率均显著低于高加索患者（7.03% vs. 14.86%，P=0.015；0% vs. 3.58%，P=0.030）。但LUSC中我国患者KEAP1突变率显著高于高加索患者（16.81% vs. 9.26%，P=0.010），而NRF2突变率无统计学差异（13.27% vs. 14.84%，P=0.654）。KEAP1突变在蛋白质序列上分布区域较离散，而NRF2突变分布相对集中于其24~34位和69~84位氨基端（Neh2结构域）。在整体肺癌患者中，KEAP1/NRF2突变患者的总生存期（overall survival，OS）显著优于非突变患者（P=0.035）。
      结论 KEAP1/NRF2在我国LUSC和LCNEC等组织学亚型中突变率较高，并可能是肺癌患者生存预后因子。该结果为靶向KEAP1/NRF2抗氧化通路的药物和诊疗策略研究提供了重要数据。

       

      Abstract:
      Background KEAP1 and NRF2 (NFE2L2) are important antioxidant stress-related genes in cells. These two gene mutations enhance the antioxidant capacity and promote the initiation and development of cancer, but it is unclear whether there are differences in their mutation status among different histological types of lung cancer.
      Method Based on the sequencing results of lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and large cell neuroendocrine carcinoma (LCNEC) cohorts, this study compared the mutation frequency, mutation type, mutation sites, and survival prognostic role of KEAP1/NRF2 mutations in LUAD, LUSC, LCNEC, and small cell lung cancer (SCLC) by combining mutations and prognostic data of The Cancer Genome Atlas (TCGA) study cohort from the cBioPortal database.
      Results The KEAP1/NRF2 mutation rates in Eastern and Western lung cancer patients were slightly different among different histologies. The KEAP1 and NRF2 mutation frequencies in LUSC and LCNEC in China were high (16.81%/13.27%; 16.39%/3.28%) versus those in LUAD (7.03%/0.0%). In patients with LUAD, the KEAP1/NRF2 gene mutation rates in Chinese patients were significantly lower than that in Caucasian patients (7.03% vs. 14.86%, P=0.015; 0% vs. 3.58%, P = 0.030). However, in Chinese LUSC patients the mutation rate of KEAP1 was significantly higher than that in Caucasian patients (16.81% vs. 9.26%, P = 0.010), while the mutation rates of NRF2 between two populations were not statistically different (13.27% vs. 14.84%, P = 0.654). KEAP1 mutations sites are scattered in the protein sequence, while NRF2 mutations sites are relatively concentrated in the amino terminus (Neh2 domain) at positions of amino acids 24~34 and 69~84. In the overall lung cancer patients, the overall survival (OS) of patients with KEAP1/NRF2 mutations was significantly better than that of patients without mutations (P=0.035).
      Conclusion KEAP1 and NRF2 gene mutation rates were relatively high in histological subtypes of LUSC and LCNEC in China, and may be a prognostic factor for survival outcome of lung cancer patients. The results provide important data for research and development of drugs targeting KEAP1/NRF2 antioxidant pathway and diagnosis and treatment strategies of lung cancer.

       

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