Proteogenomic landscape of squamous cell lung cancer

Paul A Stewart,Jamie K Teer,Matthew Chambers,Zachary Thompson,James J Saller,Yian Ann Chen,Chaomei Zhang,John M Koomen,Ram Thapa,Tania Mesa,Bin Fang,Steven A Eschrich,Katherine Fellows ,Robbert J.c Slebos ,Fredrik Pettersson,Sean Yoder,Guolin Zhang,Eric A Welsh,Yonghong Zhang,Zhihua Chen,Victoria Izumi,Amer A Beg,Theresa A Boyle,Gina M Denicola,Ling Cen,Chia-Ho Cheng,Jewel M Francis ,Eric B Haura

doi:10.1038/s41467-019-11452-x

Paul A Stewart, Jamie K Teer + Show 26 more

Open Access

https://doi.org/10.1038/s41467-019-11452-x

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Abstract

How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood. Here, we integrate DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 squamous cell lung cancer (SCC) patients. We identify three proteomic subtypes, two of which (Inflamed, Redox) comprise 87% of tumors. The Inflamed subtype is enriched with neutrophils, B-cells, and monocytes and expresses more PD-1. Redox tumours are enriched for oxidation-reduction and glutathione pathways and harbor more NFE2L2/KEAP1 alterations and copy gain in the 3q2 locus. Proteomic subtypes are not associated with patient survival. However, B-cell-rich tertiary lymph node structures, more common in Inflamed, are associated with better survival. We identify metabolic vulnerabilities (TP63, PSAT1, and TFRC) in Redox. Our work provides a powerful resource for lung SCC biology and suggests therapeutic opportunities based on redox metabolism and immune cell infiltrates.

Highlights

How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood
To begin to address this lack of knowledge, we report an integrated analysis incorporating expression proteomics with DNA copy number variation (CNV), somatic mutations, and mRNA expression levels determined by RNAseq in 108 squamous cell lung cancer (SCC) tumors, which is further informed by accompanying patient outcomes, evaluation of tumor pathology, and other clinically relevant data
Clinical characteristics were typical of this tumor type with older patients and a majority of the cohort having a history of tobacco smoking (97.2%)

Summary

Introduction

How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood. In addition to tumor autonomous features, patterns of infiltrating immune cell types have been associated with tumor progression and patient prognosis[7] Based on these results, studies such as the NCI’s Molecular Analysis for Therapy Choice (MATCH) trial are attempting to capitalize on improved molecular knowledge of SCC to employ precision medicine targeting PI3K, CDK4/6, FGFR, MET, and PD-L1. Studies such as the NCI’s Molecular Analysis for Therapy Choice (MATCH) trial are attempting to capitalize on improved molecular knowledge of SCC to employ precision medicine targeting PI3K, CDK4/6, FGFR, MET, and PD-L1 These genomic and transcriptomic alterations shape the functional proteome, control infiltration of immune cells, and present potential vulnerabilities that can be therapeutically exploited, but only after their specific roles in these molecular mechanisms is known. We discuss how the knowledge gained from proteogenomics can create a molecular classification with the potential to impact treatment strategies for SCC patients

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