Gao Hong, Yang Jun, He Lu, Wang Wei, Liu Yanhong, Hu Yue, Ge Meiling, Ding Jie, Ye Qing
Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Biobank of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Front Oncol. 2022 Jun 28;12:849024. doi: 10.3389/fonc.2022.849024. eCollection 2022.
Methylation of the promoters of and are potentially informative biomarkers for the diagnosis of early lung adenocarcinoma (LUAD). Abnormal methylation of and promoters may promote the occurrence and facilitate the progression of LUAD.
We selected 54 patients with early LUAD and 31 patients with benign lung nodules as a NJDT cohort and evaluated their DNA methylation and mRNA sequencing levels. The DNA methylation sequencing, mRNA sequencing, and clinical data for patients with LUAD were obtained from The Cancer Genome Atlas, and served as a TCGA cohort. We evaluated the diagnostic potential of a and combined promoter methylation assay for detection of early LUAD in the NJDT cohort. Then we explored the promoter methylation levels of and and their gene expression between normal and tumor samples at different stages in both cohorts. Pathways enriched between tumor and normal samples of methylation-positive patients in the NJDT cohort were analyzed.
In the NJDT cohort, the sensitivity of the combined promoter methylation assay on tumor samples was 74.07%, the sensitivity on paired tumor and paracancerous samples was 77.78%, and the specificities in both contexts were 100%. The combined promoter methylation-positive patients had clinicopathologic features including older age, larger tumors, deeper invasion, and higher Ki-67 expression. In both cohorts, expression increased and expression decreased in tumor samples. The promoter methylation level of and was significantly higher in tumor samples at stage I-II than that in normal samples. The promoter methylation levels of these two genes were both negative associated with their expression in early tumor samples. In the NJDT cohort, methylation-positive patients of both individual and assays exhibited upregulation of folate acid metabolism and nucleotide metabolism in tumor samples. The methylation-positive and methylation-positive patients showed the downregulation of pathways related to cell proliferation and apoptosis and pathways involved in DNA repair, cell growth and cell adhesion, respectively.
The combined promoter methylation assay for and can be used for screening and diagnosis of early LUAD, with good sensitivity and specificity. The promoter methylation levels of and were associated with their abnormal mRNA expression, and affected DNA instability, cell proliferation, apoptosis and tumor microenvironment in patients with LUAD.
[基因名称1]和[基因名称2]启动子的甲基化可能是早期肺腺癌（LUAD）诊断中有价值的生物标志物。[基因名称1]和[基因名称2]启动子的异常甲基化可能促进LUAD的发生并推动其进展。
我们选择了54例早期LUAD患者和31例肺良性结节患者作为NJDT队列，并评估了他们的DNA甲基化和mRNA测序水平。LUAD患者的DNA甲基化测序、mRNA测序和临床数据来自癌症基因组图谱（The Cancer Genome Atlas），作为TCGA队列。我们在NJDT队列中评估了[基因名称1]和[基因名称2]联合启动子甲基化检测对早期LUAD的诊断潜力。然后我们在两个队列中探究了不同阶段正常样本和肿瘤样本之间[基因名称1]和[基因名称2]的启动子甲基化水平及其基因表达。分析了NJDT队列中甲基化阳性患者肿瘤样本与正常样本之间富集的通路。
在NJDT队列中，联合启动子甲基化检测对肿瘤样本的敏感性为74.07%，对配对的肿瘤和癌旁样本的敏感性为77.78%，两种情况下的特异性均为100%。联合启动子甲基化阳性的患者具有包括年龄较大、肿瘤较大、浸润较深和Ki-67表达较高等临床病理特征。在两个队列中，肿瘤样本中[基因名称1]表达增加而[基因名称2]表达降低。I-II期肿瘤样本中[基因名称1]和[基因名称2]的启动子甲基化水平显著高于正常样本。这两个基因的启动子甲基化水平在早期肿瘤样本中均与其表达呈负相关。在NJDT队列中，[基因名称1]和[基因名称2]单项检测甲基化阳性的患者肿瘤样本中叶酸代谢和核苷酸代谢均上调。[基因名称1]甲基化阳性和[基因名称2]甲基化阳性的患者分别显示与细胞增殖和凋亡相关的通路以及与DNA修复、细胞生长和细胞黏附相关的通路下调。
[基因名称1]和[基因名称2]联合启动子甲基化检测可用于早期LUAD的筛查和诊断，具有良好的敏感性和特异性。[基因名称1]和[基因名称2]的启动子甲基化水平与其异常mRNA表达相关，并影响LUAD患者的DNA不稳定性、细胞增殖、凋亡和肿瘤微环境。
