肺癌中的血浆蛋白代表体：通过双向Mendelian随机化和共定位分析探索生物标志物
Plasma proteometabolome in lung cancer: exploring biomarkers through bidirectional Mendelian randomization and colocalization analysis
影响因子:3.20000
分区:生物学2区 / 生化与分子生物学3区 遗传学3区
发表日期:2024 Sep 19
作者:
Bo Dong, Mengyao Wang, Kaixiu Li, Zuwei Li, Lunxu Liu, Shensi Shen
摘要
与其他具有广泛筛查的癌症（乳房，结直肠，宫颈，前列腺和皮肤）不同，用于阳性筛查的肺结节活检与临床并发症的发病率更高。非侵入性诊断生物标志物的发展可以显着增强高危患者的肺癌管理。在这里，我们利用孟德尔随机化（MR）研究了与肺癌相关的潜在生物标志物的血浆蛋白质组和代谢组。利用双向MR和共定位分析，我们确定了新的关联，突出了血浆蛋白SFTPB和KDELC2在肺腺癌（LUAD）中的逆关系，而TCL1A的阳性关联以及与肺鳞状细胞癌（LUSC）和CNTN1的阳性关联（LUAD）与小细胞癌（LUSC）和小细胞癌（clc）。此外，我们的工作揭示了LUAD和LUSC中的代谢产物（例如鲜明的代谢产物）之间的显着负相关，以及与paraxanthine相关的比率。相反，这些癌症类型在咖啡因/帕阳性蛋白和蛛网膜酸（20：4N6）/帕阳性蛋白比中发现阳性相关性。通过正常肺组织的单细胞测序数据，我们进一步探讨了肺组织特异性蛋白SFTPB在癌变中的作用。这些发现为肺癌病因提供了新的见解，有可能指导诊断生物标志物和治疗方法的发展。
Abstract
Unlike other cancers with widespread screening (breast, colorectal, cervical, prostate, and skin), lung nodule biopsies for positive screenings have higher morbidity with clinical complications. Development of non-invasive diagnostic biomarkers could thereby significantly enhance lung cancer management for at-risk patients. Here, we leverage Mendelian Randomization (MR) to investigate the plasma proteome and metabolome for potential biomarkers relevant to lung cancer. Utilizing bidirectional MR and co-localization analyses, we identify novel associations, highlighting inverse relationships between plasma proteins SFTPB and KDELC2 in lung adenocarcinoma (LUAD) and positive associations of TCL1A with lung squamous cell carcinoma (LUSC) and CNTN1 with small cell lung cancer (SCLC). Additionally, our work reveals significant negative correlations between metabolites such as theobromine and paraxanthine, along with paraxanthine-related ratios, in both LUAD and LUSC. Conversely, positive correlations are found in caffeine/paraxanthine and arachidonate (20:4n6)/paraxanthine ratios with these cancer types. Through single-cell sequencing data of normal lung tissue, we further explore the role of lung tissue-specific protein SFTPB in carcinogenesis. These findings offer new insights into lung cancer etiology, potentially guiding the development of diagnostic biomarkers and therapeutic approaches.