PDF(Pubmed)
Abstract：
OBJECTIVE: The genomic and molecular ecology involved in the stepwise continuum progression of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) remains unclear and requires further elucidation. We aimed to characterize gene mutations and expression landscapes, and explore the association between differentially expressed genes (DEGs) and significantly mutated genes (SMGs) during the dynamic evolution from AIS to IAC.
METHODS: Thirty-five patients with ground-glass nodules (GGNs) lung adenocarcinomas were enrolled. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-Seq) were conducted on all patients, encompassing both tumor samples and corresponding noncancerous tissues. Data obtained from WES and RNA-Seq were subsequently analyzed.
RESULTS: The findings from WES delineated that the predominant mutations were observed in EGFR (49%) and ANKRD36C (17%). SMGs, including EGFR and RBM10, were associated with the dynamic evolution from AIS to IAC. Meanwhile, DEGs, including GPR143, CCR9, ADAMTS16, and others were associated with the entire process of invasive LUAD. We found that the signaling pathways related to cell migration and invasion were upregulated, and the signaling pathways of angiogenesis were downregulated across the pathological stages. Furthermore, we found that the messenger RNA (mRNA) levels of FAM83A, MAL2, DEPTOR, and others were significantly correlated with CNVs. Gene set enrichment analysis (GSEA) showed that heme metabolism and cholesterol homeostasis pathways were significantly upregulated in patients with EGFR/RBM10 co-mutations, and these patients may have poorer overall survival than those with EGFR mutations. Based on the six calculation methods for the immune infiltration score, NK/CD8+ T cells decreased, and Treg/B cells increased with the progression of early LUAD.
CONCLUSIONS: Our findings offer valuable insights into the unique genomic and molecular features of LUAD, facilitating the identification and advancement of precision medicine strategies targeting the invasive progression of LUAD from AIS to IAC.
METHODS: Thirty-five patients with ground-glass nodules (GGNs) lung adenocarcinomas were enrolled. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-Seq) were conducted on all patients, encompassing both tumor samples and corresponding noncancerous tissues. Data obtained from WES and RNA-Seq were subsequently analyzed.
RESULTS: The findings from WES delineated that the predominant mutations were observed in EGFR (49%) and ANKRD36C (17%). SMGs, including EGFR and RBM10, were associated with the dynamic evolution from AIS to IAC. Meanwhile, DEGs, including GPR143, CCR9, ADAMTS16, and others were associated with the entire process of invasive LUAD. We found that the signaling pathways related to cell migration and invasion were upregulated, and the signaling pathways of angiogenesis were downregulated across the pathological stages. Furthermore, we found that the messenger RNA (mRNA) levels of FAM83A, MAL2, DEPTOR, and others were significantly correlated with CNVs. Gene set enrichment analysis (GSEA) showed that heme metabolism and cholesterol homeostasis pathways were significantly upregulated in patients with EGFR/RBM10 co-mutations, and these patients may have poorer overall survival than those with EGFR mutations. Based on the six calculation methods for the immune infiltration score, NK/CD8+ T cells decreased, and Treg/B cells increased with the progression of early LUAD.
CONCLUSIONS: Our findings offer valuable insights into the unique genomic and molecular features of LUAD, facilitating the identification and advancement of precision medicine strategies targeting the invasive progression of LUAD from AIS to IAC.
摘要：
目的：肺腺癌（LUAD）从原位腺癌（AIS）逐步连续发展为微浸润性腺癌（MIA）和随后的浸润性腺癌（IAC）的基因组和分子生态学尚不清楚，需要进一步阐明。我们旨在表征基因突变和表达景观，并探讨从AIS到IAC的动态进化过程中差异表达基因（DEGs）和显著突变基因（SMGs）之间的关联。
方法：纳入35例磨玻璃结节（GGNs）肺腺癌患者。对所有患者进行全外显子组测序(WES)和转录组测序(RNA-Seq),包括肿瘤样本和相应的非癌组织。随后分析从WES和RNA-Seq获得的数据。
结果：来自WES的发现描绘了在EGFR（49％）和ANKRD36C（17％）中观察到的主要突变。SMGs,包括EGFR和RBM10，与从AIS到IAC的动态演变有关。同时,DEGs,包括GPR143、CCR9、ADAMTS16等均与侵入性LUAD的全过程有关。我们发现与细胞迁移和侵袭相关的信号通路上调,血管生成的信号通路在各个病理阶段都下调。此外，我们发现FAM83A的信使RNA（mRNA）水平，MAL2，深度，其他人与CNVs显著相关。基因集富集分析(GSEA)显示,EGFR/RBM10共突变患者血红素代谢和胆固醇稳态通路显著上调,与EGFR突变患者相比,这些患者的总生存期可能较差.基于免疫浸润评分的六种计算方法，NK/CD8+T细胞减少，Treg/B细胞随着早期LUAD的进展而增加。
结论：我们的发现为LUAD的独特基因组和分子特征提供了有价值的见解，促进识别和推进针对LUAD从AIS到IAC的侵入性进展的精准医学策略。
方法：纳入35例磨玻璃结节（GGNs）肺腺癌患者。对所有患者进行全外显子组测序(WES)和转录组测序(RNA-Seq),包括肿瘤样本和相应的非癌组织。随后分析从WES和RNA-Seq获得的数据。
结果：来自WES的发现描绘了在EGFR（49％）和ANKRD36C（17％）中观察到的主要突变。SMGs,包括EGFR和RBM10，与从AIS到IAC的动态演变有关。同时,DEGs,包括GPR143、CCR9、ADAMTS16等均与侵入性LUAD的全过程有关。我们发现与细胞迁移和侵袭相关的信号通路上调,血管生成的信号通路在各个病理阶段都下调。此外，我们发现FAM83A的信使RNA（mRNA）水平，MAL2，深度，其他人与CNVs显著相关。基因集富集分析(GSEA)显示,EGFR/RBM10共突变患者血红素代谢和胆固醇稳态通路显著上调,与EGFR突变患者相比,这些患者的总生存期可能较差.基于免疫浸润评分的六种计算方法，NK/CD8+T细胞减少，Treg/B细胞随着早期LUAD的进展而增加。
结论：我们的发现为LUAD的独特基因组和分子特征提供了有价值的见解，促进识别和推进针对LUAD从AIS到IAC的侵入性进展的精准医学策略。
