巴塞罗那超级计算中心Eduard Porta-Pardo团队的一项最新研究探明了精确的蛋白质基因组学揭示了种系变异对泛癌症的影响。相关论文于2025年4月14日发表在《细胞》杂志上。
研究人员研究了生殖系变异对癌症患者蛋白质组的影响，包括10种癌症类型的1064个人。研究小组引入了一种名为“精确肽组学”的方法，从患者的质谱数据中将337469种编码种系变异映射到肽上，通过利用相关蛋白质数据库揭示它们对翻译后修饰、蛋白质稳定性、等位基因特异性表达和蛋白质结构的潜在影响。研究小组在癌症基因中发现了可能影响蛋白质组学特征的罕见致病性和常见种系变异，包括改变蛋白质丰度和结构的变异以及影响磷酸化的激酶（ERBB2和MAP2K2）变异。精确肽肽分析预测信号调节蛋白α (SIRPA)和胶质原纤维酸蛋白（GFAP）的不稳定事件，分别与免疫调节和胶质母细胞瘤诊断相关。全基因组关联研究确定了基因表达和蛋白质水平的数量性状位点，跨越了数百万个SNP和蛋白质的需求。多基因风险评分与风险变异的远端影响相关。他们的发现强调了种系遗传学对癌症异质性和高通量精确肽组学的贡献。
附：英文原文
Title: Precision proteogenomics reveals pan-cancer impact of germline variants
Author: Fernanda Martins Rodrigues, Nadezhda V. Terekhanova, Kathleen J. Imbach, Karl R. Clauser, Myvizhi Esai Selvan, Isabel Mendizabal, Yifat Geffen, Yo Akiyama, Myranda Maynard, Tomer M. Yaron, Yize Li, Song Cao, Erik P. Storrs, Olivia S. Gonda, Adrian Gaite-Reguero, Akshay Govindan, Emily A. Kawaler, Matthew A. Wyczalkowski, Robert J. Klein, Berk Turhan, Karsten Krug, D.R. Mani, Felipe da Veiga Leprevost, Alexey I. Nesvizhskii, Steven A. Carr, David Feny, Michael A. Gillette, Antonio Colaprico, Antonio Iavarone, Ana I. Robles, Kuan-lin Huang, Chandan Kumar-Sinha, Franois Aguet, Alexander J. Lazar, Lewis C. Cantley, Urko M. Marigorta, Zeynep H. Gümü, Matthew H. Bailey, Gad Getz, Eduard Porta-Pardo, Li Ding, Eunkyung An, Meenakshi Anurag, Jasmin Bavarva, Chet Birger, Michael J. Birrer, Anna P. Calinawan, Michele Ceccarelli, Daniel W. Chan, Arul M. Chinnaiyan, Hanbyul Cho, Shrabanti Chowdhury, Marcin P. Cieslik, Daniel Cui Zhou, Corbin Day, Marcin J. Domagalski, Yongchao Dou, Brian J. Druker, Nathan Edwards, Matthew J. Ellis, Steven M. Foltz, Alicia Francis, Tania J. Gonzalez Robles, Sara J.C. Gosline, Runyu Hong, Galen Hostetter, Yingwei Hu, Tara Hiltke, Chen Huang, Emily Huntsman
Issue&Volume: 2025-04-14
Abstract: We investigate the impact of germline variants on cancer patients’ proteomes, encompassing 1,064 individuals across 10 cancer types. We introduced an approach, “precision peptidomics,” mapping 337,469 coding germline variants onto peptides from patients’ mass spectrometry data, revealing their potential impact on post-translational modifications, protein stability, allele-specific expression, and protein structure by leveraging the relevant protein databases. We identified rare pathogenic and common germline variants in cancer genes potentially affecting proteomic features, including variants altering protein abundance and structure and variants in kinases (ERBB2 and MAP2K2) impacting phosphorylation. Precision peptidome analysis predicted destabilizing events in signal-regulatory protein alpha (SIRPA) and glial fibrillary acid protein (GFAP), relevant to immunomodulation and glioblastoma diagnostics, respectively. Genome-wide association studies identified quantitative trait loci for gene expression and protein levels, spanning millions of SNPs and thousands of proteins. Polygenic risk scores correlated with distal effects from risk variants. Our findings emphasize the contribution of germline genetics to cancer heterogeneity and high-throughput precision peptidomics.
DOI: 10.1016/j.cell.2025.03.026
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00344-7