A proteogenomic portrait of lung squamous cell carcinoma

Clinical Proteomic Tumor Analysis Consortium

doi:10.1016/j.cell.2021.07.016

A proteogenomic portrait of lung squamous cell carcinoma

Clinical Proteomic Tumor Analysis Consortium

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.

Original language	English (US)
Pages (from-to)	4348-4371.e40
Journal	Cell
Volume	184
Issue number	16
DOIs	https://doi.org/10.1016/j.cell.2021.07.016
State	Published - Aug 5 2021

Keywords

CPTAC
acetylation
genomics
lung cancer
phosphorylation
protein
proteogenomics
proteomics
squamous
ubiquitylation

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2021.07.016

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@article{5e206c1e9e9e494cb333966b421e9952,

title = "A proteogenomic portrait of lung squamous cell carcinoma",

abstract = "Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.",

keywords = "CPTAC, acetylation, genomics, lung cancer, phosphorylation, protein, proteogenomics, proteomics, squamous, ubiquitylation",

author = "{Clinical Proteomic Tumor Analysis Consortium} and Shankha Satpathy and Karsten Krug and {Jean Beltran}, {Pierre M.} and Savage, {Sara R.} and Francesca Petralia and Chandan Kumar-Sinha and Yongchao Dou and Boris Reva and Kane, {M. Harry} and Avanessian, {Shayan C.} and Vasaikar, {Suhas V.} and Azra Krek and Lei, {Jonathan T.} and Jaehnig, {Eric J.} and Tatiana Omelchenko and Yifat Geffen and Bergstrom, {Erik J.} and Vasileios Stathias and Christianson, {Karen E.} and Heiman, {David I.} and Cieslik, {Marcin P.} and Song Cao and Xiaoyu Song and Jiayi Ji and Wenke Liu and Kai Li and Bo Wen and Yize Li and G{\"u}m{\"u}{\c s}, {Zeynep H.} and Selvan, {Myvizhi Esai} and Rama Soundararajan and Visal, {Tanvi H.} and Raso, {Maria G.} and Parra, {Edwin Roger} and {\"O}zg{\"u}n Babur and Pankaj Vats and Shankara Anand and Tobias Schraink and MacIntosh Cornwell and Rodrigues, {Fernanda Martins} and Houxiang Zhu and Mo, {Chia Kuei} and Yuping Zhang and {da Veiga Leprevost}, Felipe and Chen Huang and Chinnaiyan, {Arul M.} and Li, {Qing Kay} and Chan, {Daniel W.} and Hui Zhang and Zhen Zhang",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = aug,

day = "5",

doi = "10.1016/j.cell.2021.07.016",

language = "English (US)",

volume = "184",

pages = "4348--4371.e40",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "16",

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TY - JOUR

T1 - A proteogenomic portrait of lung squamous cell carcinoma

AU - Clinical Proteomic Tumor Analysis Consortium

AU - Satpathy, Shankha

AU - Krug, Karsten

AU - Jean Beltran, Pierre M.

AU - Savage, Sara R.

AU - Petralia, Francesca

AU - Kumar-Sinha, Chandan

AU - Dou, Yongchao

AU - Reva, Boris

AU - Kane, M. Harry

AU - Avanessian, Shayan C.

AU - Vasaikar, Suhas V.

AU - Krek, Azra

AU - Lei, Jonathan T.

AU - Jaehnig, Eric J.

AU - Omelchenko, Tatiana

AU - Geffen, Yifat

AU - Bergstrom, Erik J.

AU - Stathias, Vasileios

AU - Christianson, Karen E.

AU - Heiman, David I.

AU - Cieslik, Marcin P.

AU - Cao, Song

AU - Song, Xiaoyu

AU - Ji, Jiayi

AU - Liu, Wenke

AU - Li, Kai

AU - Wen, Bo

AU - Li, Yize

AU - Gümüş, Zeynep H.

AU - Selvan, Myvizhi Esai

AU - Soundararajan, Rama

AU - Visal, Tanvi H.

AU - Raso, Maria G.

AU - Parra, Edwin Roger

AU - Babur, Özgün

AU - Vats, Pankaj

AU - Anand, Shankara

AU - Schraink, Tobias

AU - Cornwell, MacIntosh

AU - Rodrigues, Fernanda Martins

AU - Zhu, Houxiang

AU - Mo, Chia Kuei

AU - Zhang, Yuping

AU - da Veiga Leprevost, Felipe

AU - Huang, Chen

AU - Chinnaiyan, Arul M.

AU - Li, Qing Kay

AU - Chan, Daniel W.

AU - Zhang, Hui

AU - Zhang, Zhen

PY - 2021/8/5

Y1 - 2021/8/5

N2 - Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.

AB - Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.

KW - CPTAC

KW - acetylation

KW - genomics

KW - lung cancer

KW - phosphorylation

KW - protein

KW - proteogenomics

KW - proteomics

KW - squamous

KW - ubiquitylation

UR - http://www.scopus.com/inward/record.url?scp=85111677413&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85111677413&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.07.016

DO - 10.1016/j.cell.2021.07.016

M3 - Article

C2 - 34358469

AN - SCOPUS:85111677413

SN - 0092-8674

VL - 184

SP - 4348-4371.e40

JO - Cell

JF - Cell

IS - 16

ER -

A proteogenomic portrait of lung squamous cell carcinoma

Abstract

Keywords

ASJC Scopus subject areas

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