Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy.
Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy.
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DOI：
10.1016/j.cell.2020.10.036
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发表时间：
2020-11-25
期刊：
影响因子：
64.5
通讯作者：
Clinical Proteomic Tumor Analysis Consortium
中科院分区：
文献类型：
--
作者：
Krug K;Jaehnig EJ;Satpathy S;Blumenberg L;Karpova A;Anurag M;Miles G;Mertins P;Geffen Y;Tang LC;Heiman DI;Cao S;Maruvka YE;Lei JT;Huang C;Kothadia RB;Colaprico A;Birger C;Wang J;Dou Y;Wen B;Shi Z;Liao Y;Wiznerowicz M;Wyczalkowski MA;Chen XS;Kennedy JJ;Paulovich AG;Thiagarajan M;Kinsinger CR;Hiltke T;Boja ES;Mesri M;Robles AI;Rodriguez H;Westbrook TF;Ding L;Getz G;Clauser KR;Fenyö D;Ruggles KV;Zhang B;Mani DR;Carr SA;Ellis MJ;Gillette MA;Clinical Proteomic Tumor Analysis Consortium
基于质谱的蛋白质组学与下一代DNA和RNA测序的整合可以更全面地分析肿瘤。在这里，这种“蛋白基因组学”方法应用于122例未经治疗的原发性乳腺癌，以保留翻译后修饰，包括蛋白磷酸化和乙酰化。蛋白基因组学挑战了标准乳腺癌诊断，提供了ERBB 2扩增子的详细分析，定义了可能从免疫检查点治疗中获益的肿瘤亚群，并允许更准确地评估Rb状态以预测CDK 4/6抑制剂的反应性。磷酸化蛋白质组学研究揭示了肿瘤抑制基因缺失和靶向激酶之间的新联系，乙酰化蛋白质组学分析强调了参与DNA损伤反应的关键核蛋白的乙酰化，并揭示了细胞质和线粒体乙酰化与代谢之间的相互作用。我们的研究结果强调了蛋白质基因组学的潜力，乳腺癌的临床研究，通过更准确的注释的靶向途径和生物学特征，这种显着的异质性恶性肿瘤。乳腺癌是一种高度异质性的疾病，具有可变的结果和亚型驱动的治疗方法，使精准医学成为一个相当大的挑战。122例原发性乳腺癌的蛋白基因组学分析提供了对临床相关生物学的见解，包括细胞周期失调、肿瘤免疫原性、异常代谢和治疗靶点表达的异质性。
The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this “proteogenomics” approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases.Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy. Breast cancer is a highly heterogeneous disease with variable outcomes and subtype-driven treatment approaches, making precision medicine a considerable challenge. Proteogenomic analyses of 122 primary breast cancers provide insights into clinically relevant biology, including cell cycle dysregulation, tumor immunogenicity, aberrant metabolism, and heterogeneity in therapeutic target expression.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
4.7
作者：
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通讯作者：
Caldon CE
影响因子：
2
作者：
Chen X;Li J;Gray WH;Lehmann BD;Bauer JA;Shyr Y;Pietenpol JA
通讯作者：
Pietenpol JA
影响因子：
10.3
作者：
Anurag, Meenakshi;Zhu, Mayanne;Ellis, Matthew J.
通讯作者：
Ellis, Matthew J.