Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.
EBioMedicine. 2021 Dec;74:103714. doi: 10.1016/j.ebiom.2021.103714. Epub 2021 Nov 22.
Molecular features underlining the multistage progression of gastric lesions and development of early gastric cancer (GC) are poorly understood, restricting the ability to GC prevention and management.
We portrayed proteomic landscape and explored proteomic signatures associated with progression of gastric lesions and risk of early GC. Tissue proteomic profiling was conducted for a total of 324 subjects. A case-control study was performed in the discovery stage (n=169) based on populations from Linqu, a known high-risk area for GC in China. We then conducted two-stage validation, including a cohort study from Linqu (n = 56), with prospective follow-up for progression of gastric lesions (280-473 days), and an independent case-control study from Beijing (n = 99).
There was a clear distinction in proteomic features for precancerous gastric lesions and GC. We derived four molecular subtypes of gastric lesions and identified subtype-S4 with the highest progression risk. We found 104 positively-associated and 113 inversely-associated proteins for early GC, with APOA1BP, PGC, HPX and DDT associated with the risk of gastric lesion progression. Integrating these proteomic signatures, the ability to predict progression of gastric lesions was significantly strengthened (areas-under-the-curve=0.88 (95%CI: 0.78-0.99) vs. 0.56 (0.36-0.76), Delong's P = 0.002). Immunohistochemistry assays and examination at mRNA level validated the findings for four proteins.
We defined proteomic signatures for progression of gastric lesions and risk of early GC, which may have translational significance for identifying particularly high-risk population and detecting GC at an early stage, improving potential for targeted GC prevention.
The funders are listed in the Acknowledgement.
胃病变和早期胃癌（GC）发展的多阶段进展的分子特征了解甚少，限制了 GC 预防和管理的能力。
我们描绘了蛋白质组学景观，并探索了与胃病变进展和早期 GC 风险相关的蛋白质组学特征。对总共 324 名受试者进行了组织蛋白质组学分析。在发现阶段（n=169）进行了一项基于中国已知 GC 高危地区临朐人群的病例对照研究。然后我们进行了两阶段验证，包括来自临朐的队列研究（n=56），前瞻性随访胃病变进展（280-473 天），以及来自北京的独立病例对照研究（n=99）。
癌前胃病变和 GC 的蛋白质组学特征明显不同。我们得出了四种胃病变的分子亚型，并确定了具有最高进展风险的亚型-S4。我们发现 104 个与早期 GC 呈正相关和 113 个与早期 GC 呈负相关的蛋白质，APOA1BP、PGC、HPX 和 DDT 与胃病变进展的风险相关。整合这些蛋白质组学特征，预测胃病变进展的能力显著增强（曲线下面积=0.88（95%CI：0.78-0.99）与 0.56（0.36-0.76），Delong's P=0.002）。免疫组织化学检测和 mRNA 水平检测验证了这四种蛋白质的发现。
我们定义了胃病变进展和早期 GC 风险的蛋白质组学特征，这可能对识别高危人群和早期检测 GC 具有转化意义，提高了有针对性的 GC 预防的潜力。
资助者列在致谢中。
