肺癌血浆蛋白质组代谢组：通过双向孟德尔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

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HUMAN MOLECULAR GENETICS

影响因子:3.2

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

DOI: 10.1093/hmg/ddae110

摘要

与其他广泛筛查的癌症（乳腺癌、结直肠癌、宫颈癌、前列腺癌和皮肤癌）不同，肺结节阳性筛查的活检具有更高的发病率和临床并发症。因此，发展无创诊断生物标志物将显著提升高危患者的肺癌管理。在此，我们利用孟德尔随机化（MR）研究血浆蛋白质组和代谢组，以寻找与肺癌相关的潜在生物标志物。通过双向MR和共定位分析，我们发现了新的关联，突显了肺腺癌（LUAD）中血浆蛋白SFTPB与KDELC2的反向关系，以及TCL1A与肺鳞癌（LUSC）、CNTN1与小细胞肺癌（SCLC）的正向关联。此外，我们还揭示了如可可碱和对甲氧基苯甲酸等代谢物在LUAD和LUSC中的显著负相关，以及与咖啡因/对甲氧基苯甲酸比率相关的正相关关系。利用正常肺组织单细胞测序数据，我们进一步探讨了肺组织特异性蛋白SFTPB在癌变中的作用。这些发现为肺癌的病因提供了新的见解，可能有助于指导诊断生物标志物和治疗策略的开发。

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.