Precision proteogenomics reveals pan-cancer impact of germline variants

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-04-14 DOI:10.1016/j.cell.2025.03.026

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, Yige Wu

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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.

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精准蛋白质基因组学揭示种系变异对泛癌症的影响

我们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1,064个人。我们引入了一种名为“精确肽组学”的方法，从患者的质谱数据中将337,469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。我们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，跨越数百万个snp和数千种蛋白质。多基因风险评分与风险变异的远端影响相关。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确肽组学的贡献。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.