乳腺癌变与靶点的蛋白质基因全面分析
蛋白质组学是对蛋白质结构和功能的全面分析，基因组学是对全部DNA遗传信息的全面分析，转录组学是对全部RNA转录信息的全面分析。蛋白质基因组学结合了蛋白质组学质谱分析、DNA和RNA大规模并行测序，可对肿瘤形成及其靶点进行更全面的分析。
2020年11月18日，全球自然科学三大旗舰期刊之一、美国《细胞》正刊发表麻省理工学院哈佛大学布罗德研究所、贝勒医学院、纽约大学、圣路易斯华盛顿大学、哥伦比亚大学、迈阿密大学、弗雷德哈钦森癌症研究中心、国家癌症研究所、麻省总医院、波兰波兹南医学大学国际分子肿瘤学研究所的临床蛋白质组学肿瘤分析联盟（CPTAC）研究报告，全面分析了乳腺癌变过程及其靶向治疗的蛋白质基因组学，全文长达53页。
该研究前瞻收集了122例原发乳腺癌治疗前的肿瘤标本，利用蛋白质基因组学方法，对蛋白质磷酸化和乙酰化等蛋白质翻译后化学修饰进行全面分析。
结果发现，蛋白质基因组学挑战了乳腺癌的诊断标准，能够对致癌基因HER2大量复制而使拷贝数不断增多的DNA或RNA序列进行详细分析，确定可能对免疫检查点治疗获益的管腔型乳腺癌亚组患者，并实现更精准地评定抑癌基因Rb状态，以预测CDK4/6抑制剂疗效。
蛋白质磷酸化组学分析发现，抑癌基因缺失与可靶向激酶之间存在新的关联。而蛋白质乙酰化组学分析突显了乙酰化对DNA损伤应答关键核蛋白的作用，并揭示了细胞质和线粒体乙酰化与代谢之间的相互影响。
因此，该研究结果表明，蛋白质基因组学能够更精准地分析乳腺癌的可靶向蛋白质信号通路和生物学特征，突显了其对乳腺癌临床研究的巨大潜力。
Cell. 2020 Nov 18. Online ahead of print.
Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy.
Karsten Krug, Eric J. Jaehnig, Shankha Satpathy, Lili Blumenberg, Alla Karpova, Meenakshi Anurag, George Miles, Philipp Mertins, Yifat Geffen, Lauren C. Tang, David I. Heiman, Song Cao, Yosef E. Maruvka, Jonathan T. Lei, Chen Huang, Ramani B. Kothadia, Antonio Colaprico, Chet Birger, Jarey Wang, Yongchao Dou, Bo Wen, Zhiao Shi, Yuxing Liao, Maciej Wiznerowicz, Matthew A. Wyczalkowski, Xi Steven Chen, Jacob J. Kennedy, Amanda G. Paulovich, Mathangi Thiagarajan, Christopher R. Kinsinger, Tara Hiltke, Emily S. Boja, Mehdi Mesri, Ana I. Robles, Henry Rodriguez, Thomas F. Westbrook, Li Ding, Gad Getz, Karl R. Clauser, David Fenyo, Kelly V. Ruggles, Bing Zhang, D.R. Mani, Steven A. Carr, Matthew J. Ellis, Michael A. Gillette; Clinical Proteomic Tumor Analysis Consortium.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Baylor College of Medicine, Houston, TX, USA; NYU Grossman School of Medicine, New York, NY, USA; Washington University in St. Louis, St. Louis, MO, USA; Columbia University, New York, NY, USA; University of Miami Miller School of Medicine, Miami, FL, USA; Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA; National Cancer Institute, Bethesda, MD, USA; Massachusetts General Hospital, Charlestown, MA, USA; Massachusetts General Hospital, Boston, MA, USA; Max Delbrück Center for Molecular Medicine in the Helmholtz Society and Berlin Institute of Health, Berlin, Germany; Poznan University of Medical Sciences, Poznań, Poland; International Institute for Molecular Oncology, Poznań, Poland.
HIGHLIGHTS
Comprehensive proteogenomics resource from prospectively collected breast tumors
Proteogenomics defines ERBB2 and Rb status with clinical implications
Acetylproteome profiling yields insights into subtype-specific cancer metabolism
Immune profiling nominates subsets of luminal tumors for immune therapy
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.
KEYWORDS: CPTAC; proteogenomics; breast cancer; genomics; proteomics; phosphoproteomics; acetylation; mass spectrometry; immune checkpoint therapy; CDK 4/6 inhibitors
DOI: 10.1016/j.cell.2020.10.036