Martins Rodrigues Fernanda, Terekhanova Nadezhda V, Imbach Kathleen J, Clauser Karl R, Esai Selvan Myvizhi, Mendizabal Isabel, Geffen Yifat, Akiyama Yo, Maynard Myranda, Yaron Tomer M, Li Yize, Cao Song, Storrs Erik P, Gonda Olivia S, Gaite-Reguero Adrian, Govindan Akshay, Kawaler Emily A, Wyczalkowski Matthew A, Klein Robert J, Turhan Berk, Krug Karsten, Mani D R, Leprevost Felipe da Veiga, Nesvizhskii Alexey I, Carr Steven A, Fenyö David, Gillette Michael A, Colaprico Antonio, Iavarone Antonio, Robles Ana I, Huang Kuan-Lin, Kumar-Sinha Chandan, Aguet François, Lazar Alexander J, Cantley Lewis C, Marigorta Urko M, Gümüş Zeynep H, Bailey Matthew H, Getz Gad, Porta-Pardo Eduard, Ding Li
Department of Medicine, Washington University in St. Louis, Saint Louis, MO, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain; Universitat Autonoma de Barcelona, Barcelona, Spain.
Cell. 2025 May 1;188(9):2312-2335.e26. doi: 10.1016/j.cell.2025.03.026. Epub 2025 Apr 14.
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.
我们研究了种系变异对癌症患者蛋白质组的影响，涵盖了10种癌症类型的1064名个体。我们引入了一种“精准肽组学”方法，将337,469个编码种系变异映射到患者质谱数据中的肽段上，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。我们在癌症基因中鉴定出可能影响蛋白质组特征的罕见致病和常见种系变异，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。精准肽组分析预测了信号调节蛋白α（SIRPA）和胶质纤维酸性蛋白（GFAP）中的不稳定事件，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，涵盖数百万个单核苷酸多态性（SNP）和数千种蛋白质。多基因风险评分与风险变异的远端效应相关。我们的研究结果强调了种系遗传学对癌症异质性和高通量精准肽组学的贡献。
Genes (Basel). 2025-6-30
Cancer Cell. 2023-8-14
Int J Mol Sci. 2023-4-25
Orphanet J Rare Dis. 2023-5-7
Signal Transduct Target Ther. 2023-3-1
NPJ Precis Oncol. 2023-1-27
Zotero 插件