非小肺癌中血液 FOLR3 甲基化异常和异质性突显了其与肺鳞癌的密切联系

IF 4.7 2区医学 Q1 RESPIRATORY SYSTEM

Respiratory Research Pub Date : 2024-01-25 DOI:10.1186/s12931-024-02691-8

Yunhui Qu, Xiuzhi Zhang, Rong Qiao, Feifei Di, Yakang Song, Jun Wang, Longtao Ji, Jie Zhang, Wanjian Gu, Yifei Fang, Baohui Han, Rongxi Yang, Liping Dai, Songyun Ouyang

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引用次数: 0

摘要

非小细胞肺癌（NSCLC）占肺癌的绝大多数。早期发现对于降低肺癌相关死亡率至关重要。DNA 甲基化异常发生在癌变的早期，并可在血液中检测到。研究血液甲基化失调标志物对于早期诊断 NSCLC 至关重要。通过对外周血样本进行 Illumina 850K 阵列分析，筛选出了与 NSCLC 相关的甲基化基因叶酸受体γ（FOLR3）。质谱法在两项独立的病例对照研究中进行了验证（验证 I：n = 2548；验证 II：n = 3866）。研究对象包括肺鳞癌（LUSC）或肺腺癌（LUAD）患者、正常对照组（NCs）和良性肺结节（BPN）病例。比较了不同人群的 FOLR3 甲基化情况。研究了它们与 NSCLC 临床特征的关系。研究人员进行了接收者操作特征分析、Kruskal-Wallis 检验、Wilcoxon 检验、物流回归分析和提名图分析。在发现轮中，FOLR3的两个CpG位点（CpG_1和CpG_2）在NSCLC患者中的甲基化程度明显低于NCs。在两次验证中，LUSC 和 LUAD 患者都出现了明显的 FOLR3 低甲基化。LUSC患者的CpG_1和CpG_2甲基化水平明显低于BPN病例和LUAD患者。在两次验证中，CpG_1甲基化和CpG_2甲基化都能很好地区分LUSC和NC，验证I的曲线下面积（AUC）分别为0.818和0.832，验证II的曲线下面积（AUC）分别为0.789和0.780。它们也能区分 LUAD 和 NC，但效率较低。在两次验证中，CpG_1 和 CpG_2 甲基化也能很好地区分 LUSC 和 BPNs。通过两次验证的合并数据集，年龄、性别和 FOLR3 甲基化与 LUSC 和 LUAD 风险的独立相关性得到了证实，年龄-性别-CpG_1 特征可以将 LUSC 和 LUAD 与 NCs 和 BPNs 区分开来，其中 LUSC 的区分效率更高。在LUSC和LUAD中显示了基于血液的FOLR3低甲基化。LUSC和LUAD之间的FOLR3甲基化异质性突显了它与LUSC的关联性更强。FOLR3甲基化和年龄-性别-CpG_1特征可能是早期检测NSCLC（尤其是LUSC）的新型诊断标志物。

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Blood FOLR3 methylation dysregulations and heterogeneity in non-small lung cancer highlight its strong associations with lung squamous carcinoma

Non-small cell lung cancer (NSCLC) accounts for the vast majority of lung cancers. Early detection is crucial to reduce lung cancer-related mortality. Aberrant DNA methylation occurs early during carcinogenesis and can be detected in blood. It is essential to investigate the dysregulated blood methylation markers for early diagnosis of NSCLC. NSCLC-associated methylation gene folate receptor gamma (FOLR3) was selected from an Illumina 850K array analysis of peripheral blood samples. Mass spectrometry was used for validation in two independent case–control studies (validation I: n = 2548; validation II: n = 3866). Patients with lung squamous carcinoma (LUSC) or lung adenocarcinoma (LUAD), normal controls (NCs) and benign pulmonary nodule (BPN) cases were included. FOLR3 methylations were compared among different populations. Their associations with NSCLC clinical features were investigated. Receiver operating characteristic analyses, Kruskal–Wallis test, Wilcoxon test, logistics regression analysis and nomogram analysis were performed. Two CpG sites (CpG_1 and CpG_2) of FOLR3 was significantly lower methylated in NSCLC patients than NCs in the discovery round. In the two validations, both LUSC and LUAD patients presented significant FOLR3 hypomethylations. LUSC patients were highlighted to have significantly lower methylation levels of CpG_1 and CpG_2 than BPN cases and LUAD patients. Both in the two validations, CpG_1 methylation and CpG_2 methylation could discriminate LUSC from NCs well, with areas under the curve (AUCs) of 0.818 and 0.832 in validation I, and 0.789 and 0.780 in validation II. They could also differentiate LUAD from NCs, but with lower efficiency. CpG_1 and CpG_2 methylations could also discriminate LUSC from BPNs well individually in the two validations. With the combined dataset of two validations, the independent associations of age, gender, and FOLR3 methylation with LUSC and LUAD risk were shown and the age-gender-CpG_1 signature could discriminate LUSC and LUAD from NCs and BPNs, with higher efficiency for LUSC. Blood-based FOLR3 hypomethylation was shown in LUSC and LUAD. FOLR3 methylation heterogeneity between LUSC and LUAD highlighted its stronger associations with LUSC. FOLR3 methylation and the age-gender-CpG_1 signature might be novel diagnostic markers for the early detection of NSCLC, especially for LUSC.

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Respiratory Research 医学-呼吸系统

自引率

1.70%

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314

期刊介绍： Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.