Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

被引：300

作者：

Krug, Karsten ^{[1
]}

Jaehnig, Eric J. ^{[2
,3
]}

Satpathy, Shankha ^{[1
]}

Blumenberg, Lili ^{[4
,5
]}

Karpova, Alla ^{[6
]}

Anurag, Meenakshi ^{[2
,3
]}

Miles, George ^{[2
,3
]}

Mertins, Philipp ^{[1
,7
,8
]}

Geffen, Yifat ^{[1
]}

Tang, Lauren C. ^{[1
,9
]}

Heiman, David, I ^{[1
]}

Cao, Song ^{[6
]}

Maruvka, Yosef E. ^{[1
]}

Lei, Jonathan T. ^{[2
,3
]}

Huang, Chen ^{[2
,3
]}

Kothadia, Ramani B. ^{[1
]}

Colaprico, Antonio ^{[10
]}

Birger, Chet ^{[1
]}

Wang, Jarey ^{[11
,12
]}

Dou, Yongchao ^{[2
,3
]}

Wen, Bo ^{[2
,3
]}

Shi, Zhiao ^{[2
,3
]}

Liao, Yuxing ^{[2
,3
]}

Wiznerowicz, Maciej ^{[13
,14
]}

Wyczalkowski, Matthew A. ^{[6
]}

Chen, Xi Steven ^{[10
]}

Kennedy, Jacob J. ^{[15
]}

Paulovich, Amanda G. ^{[15
]}

Thiagarajan, Mathangi ^{[16
]}

Kinsinger, Christopher R. ^{[17
]}

Hiltke, Tara ^{[17
]}

Boja, Emily S. ^{[17
]}

Mesri, Mehdi ^{[17
]}

Robles, Ana, I ^{[17
]}

Rodriguez, Henry ^{[17
]}

Westbrook, Thomas F. ^{[11
,12
]}

Ding, Li ^{[6
]}

Getz, Gad ^{[1
,18
]}

Clauser, Karl R. ^{[1
]}

Fenyo, David ^{[19
]}

Ruggles, Kelly, V ^{[4
,5
]}

Zhang, Bing ^{[2
,3
]}

Mani, D. R. ^{[1
]}

Carr, Steven A. ^{[1
]}

Ellis, Matthew J. ^{[2
,3
]}

Gillette, Michael A. ^{[1
,20
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[2] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA

[3] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA

[4] NYU, Grossman Sch Med, Inst Syst Genet, New York, NY 10016 USA

[5] NYU, Grossman Sch Med, Dept Med, New York, NY 10016 USA

[6] Washington Univ, Dept Med & Genet, Siteman Canc Ctr, St Louis, MO 63110 USA

[7] Max Delbruck Ctr Mol Med Helmholtz Soc, Berlin, Germany

[8] Berlin Inst Hlth, Berlin, Germany

[9] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA

[10] Univ Miami, Miller Sch Med, Div Biostat, Dept Publ Hlth Sci, Miami, FL 33136 USA

[11] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Dept Mol & Human Genet, Houston, TX 77030 USA

[12] Baylor Coll Med, Therapeut Innovat Ctr, Houston, TX 77030 USA

[13] Poznan Univ Med Sci, PL-61701 Poznan, Poland

[14] Int Inst Mol Oncol, PL-60203 Poznan, Poland

[15] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA

[16] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA

[17] NCI, Off Canc Clin Prote Res, Bethesda, MD 20892 USA

[18] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02114 USA

[19] NYU, Grossman Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA

[20] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA

来源：

CELL | 2020年 / 183卷 / 05期

关键词：

QUANTITATIVE PROTEOMICS; INTEGRATIVE ANALYSIS; PANCREATIC-CANCER; SOMATIC MUTATIONS; CELL-CYCLE; EXPRESSION; REVEALS; GENOME; ACETYLATION; GENES;

D O I：

10.1016/j.cell.2020.10.036

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. Acetyl proteome 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.

引用

页码：1436 / +

页数：52

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