Rao Wen, Zhang Qin, Dai Xiaoyan, Yang Yuxin, Lei Zhang, Kuang Xunjie, Xiao He, Zhu Jianwu, Xiong Yanli, Wang Dong, Yang Lujie
Cancer Center, Daping Hospital and Army Medical Center of PLA, Army Medical University, No.10 Changjiangzhi Rd, Yuzhong District, Chongqing, People's Republic of China.
The 75th Group Army Hospital, Dali, Yunnan, People's Republic of China.
Sci Rep. 2025 May 13;15(1):16647. doi: 10.1038/s41598-025-98088-8.
Unrepaired DNA damage is the initiation of mutation and tumor-specific biological characteristics. Oxidative stress and base excision repair (BER) are the two main pathways to cope with oxidative DNA damage, which is closely related to the heterogeneity of Lung adenocarcinoma (LUAD), but their relationship with tumor biological characteristics is unclear, and a molecular subtyping based on comprehensive BER and oxidative stress gene expression is lacking. 501 samples from The Cancer Genome Atlas (TCGA) were classified into three subtypes based on genes related to BER and oxidative stress through hierarchical agglomerative cluster analysis. By integrating the nearest template prediction (NTP), four GEO datasets and 52 samples from our institution were analyzed for validation. Bioinformatic analysis was performed to define the diverse molecular characteristics, mutation background, tumor microenvironment, and prognosis. Three subtypes with distinct gene signatures were identified: relatively high BER and low oxidative stress gene expression (C1), low BER gene and high oxidative stress gene expression (C2), and high expression of both BER and oxidative stress genes (C3). C2 was characterized by a low mutation frequency in TP53 (29%) and a high mutation frequency in EGFR (20%), whereas a high frequency of mutation was seen in C3 in STK11 and KEAP1 genes. Additionally, differentially expressed genes among the three subtypes were particularly enriched in immune-related pathways, and the abundance of immune cells and Immunophenoscore were significantly higher in C2, while the Tumor Immune Dysfunction and Exclusion (TIDE) score was lower in C2, indicating a better response to immunotherapy. C2 was also associated with an improved survival outcome compared with C1 and C3, and this finding was validated in 978 samples from four independent GEO datasets and 52 samples at our institution by the NTP algorithm. The three-subtype classifications based on BER and oxidative stress gene expression offers potential for predicting the survival and response to immunotherapy of LUAD patients.
未修复的DNA损伤是突变和肿瘤特异性生物学特征的起始因素。氧化应激和碱基切除修复（BER）是应对氧化性DNA损伤的两条主要途径，这与肺腺癌（LUAD）的异质性密切相关，但其与肿瘤生物学特征的关系尚不清楚，且缺乏基于BER和氧化应激基因综合表达的分子亚型分类。通过层次聚类分析，将来自癌症基因组图谱（TCGA）的501个样本根据与BER和氧化应激相关的基因分为三个亚型。通过整合最近模板预测（NTP），对四个GEO数据集和来自我们机构的52个样本进行分析以进行验证。进行生物信息学分析以确定不同的分子特征、突变背景、肿瘤微环境和预后。确定了具有不同基因特征的三个亚型：BER相对较高且氧化应激基因表达较低（C1）、BER基因较低且氧化应激基因表达较高（C2）以及BER和氧化应激基因均高表达（C3）。C2的特征是TP53突变频率低（29%）而EGFR突变频率高（20%），而C3中STK11和KEAP1基因的突变频率较高。此外，三个亚型之间的差异表达基因在免疫相关途径中特别富集，免疫细胞丰度和免疫表型评分在C2中显著更高，而肿瘤免疫功能障碍和排除（TIDE）评分在C2中较低，表明对免疫治疗反应更好。与C1和C3相比，C2还与改善的生存结果相关，这一发现在来自四个独立GEO数据集的978个样本和我们机构的52个样本中通过NTP算法得到了验证。基于BER和氧化应激基因表达的三亚型分类为预测LUAD患者的生存和对免疫治疗的反应提供了潜力。
