Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression

Chen, Yi Ju; Roumeliotis, Theodoros I.; Chang, Yun‐chien; Chen, Ching Tai; Han, Chia Li; Lin, Miao; Chen, Huei‐Wen; Chang, Gee Chen; Chang, Yih‐Leong; Wu, Chen; Lin, Mong-Wei; Hsieh, Min Shu; Wang, Yu Tai; Chen, Yet Ran; Jonassen, Inge; Ghavidel, Fatemeh Zamanzad; Lin, Ze Shiang; Lin, Kuen Tyng; Chen, Ching Wen; Sheu, Pei Yuan; Hung, Chi‐Ren; Huang, Ke; Yang, Hao; Lin, Pei; Yen, Ta Chi; Lin, Yi; Wang, Jen Hung; Raghav, Lovely; Lin, Chien Yu; Chen, Yan Si; Wu, Pei‐Ju; Lai, Chi Ting; Weng, Shao Hsing; Su, Kang-Yi; Chang, Wei Hung; Tsai, Pang-Yen; Robles, Ana I.; Rodriguez, Henry; Hsiao, Yi-Jing; Chang, Wen Hsin; Sung, Ting Yi; Chen, Jin‐Shing; Yu, Sung-Liang; Choudhary, Jyoti S.; Chen, Hsuan Yu; Yang, Pan Chyr; Chen, Yu‐Ju

doi:10.1016/j.cell.2020.06.012

Cited by 243 publications

(242 citation statements)

References 98 publications

(114 reference statements)

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“…focused on early-stage, predominantly female and non-smoking lung adenocarcinoma and illuminated the molecular phenotype of this demographically distinct disease (14).…”

Section: Discussionmentioning

confidence: 99%

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Proteomic Analyses Identify Differentially Expressed Proteins and Pathways Between Low-Risk and High-Risk Subtypes of Early-Stage Lung Adenocarcinoma and Their Prognostic Impacts

Zhou

Liu

et al. 2021

Molecular & Cellular Proteomics

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The histopathological subtype of lung adenocarcinoma (LUAD) is closely associated with prognosis. Micropapillary or solid predominant LUAD tends to relapse after surgery at an early stage, whereas lepidic pattern shows a favorable outcome. However, the molecular mechanism underlying this phenomenon remains unknown. Here, we recruited 31 lepidic predominant LUADs (LR: low-risk subtype group) and 28 micropapillary or solid predominant LUADs (HR: high-risk subtype group). Tissues of these cases were obtained and label-free quantitative proteomic and bioinformatic analyses were performed. Additionally, prognostic impact of targeted proteins was validated using The Cancer Genome Atlas databases (n=492) and tissue microarrays composed of early-stage LUADs (n=228). A total of 192 differentially expressed proteins were identified between tumor tissues of LR and HR and three clusters were identified via hierarchical clustering excluding eight proteins. Cluster 1 (65 proteins) showed a sequential decrease in expression from normal tissues to tumor tissues of LR and then to HR and was predominantly enriched in pathways such as tyrosine metabolism and ECM-receptor interaction, and increased matched mRNA expression of 18 proteins from this cluster predicted favorable prognosis. Cluster 2 (70 proteins) demonstrated a sequential increase in expression from normal tissues to tumor tissues of LR and then to HR and was mainly enriched in pathways such as extracellular organization, DNA replication and cell cycle, and high matched mRNA expression of 25 proteins indicated poor prognosis. Cluster 3 (49 proteins) showed high expression only in LR, with high matched mRNA expression of 20 proteins in this cluster indicating favorable prognosis. Furthermore, high expression of ERO1A and FEN1 at protein level predicted poor prognosis in early-stage LUAD, supporting the mRNA results. In conclusion, we discovered key differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage LUAD. Some of these proteins could serve as potential biomarkers in prognostic evaluation.

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“…focused on early-stage, predominantly female and non-smoking lung adenocarcinoma and illuminated the molecular phenotype of this demographically distinct disease (14).…”

Section: Discussionmentioning

confidence: 99%

“…Systematical therapeutic candidates were discovered in LUADs featured with driver events (13). Chen et al focused on the proteogenomic landscape of early-stage and non-smoking LUAD in East Asia (14). They also identified three molecular subtypes from multi-omic profiles and distinguished clinical features within early stage.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Analyses Identify Differentially Expressed Proteins and Pathways Between Low-Risk and High-Risk Subtypes of Early-Stage Lung Adenocarcinoma and Their Prognostic Impacts

Zhou

Liu

et al. 2021

Molecular & Cellular Proteomics

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“…TP53, STK11, RB1 , and APC etc.) in LUAD patients from East Asia [ 55 , 56 ] and enriched in female and younger non-smoking LUADs [55] , highlighting the broad functional and clinical significance of RBM10 mutations in LUAD. Besides mutations, we examined the RBM10 expression in TCGA LUAD samples without RBM10 mutation and found that 12.8% of RBM10 wild type LUAD samples had lower RBM10 expression than the median of RBM10 -mutant LUADs (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H

et al. 2020

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Background RNA splicing defects are emerging molecular hallmarks of cancer. The gene encoding splicing factor RNA binding motif protein 10 (RBM10) has been found frequently mutated in various types of cancer, particularly lung adenocarcinoma (LUAD), but how RBM10 affects cancer pathogenesis remains to be determined. Moreover, the functional roles and clinical significance of RBM10 mutation-associated splicing events in LUAD are largely unknown. Methods RBM10 mutations and their functional impacts were examined in LUAD patients from a Chinese patient cohort and The Cancer Genome Atlas (TCGA). Alternative splicing (AS) changes induced by RBM10 mutations in LUAD were identified by RNA sequencing and correlated with patient survival. Functions of RBM10 and the splice variants of eukaryotic translation initiation factor 4H containing or lacking exon 5 ( EIF4H-L and EIF4H-S respectively) in LUAD development and progression were examined by cellular phenotypic assays and xenograft tumour formation. Findings RBM10 mutations in LUAD generally lead to loss-of-function and cause extensive alterations in splicing events that can serve as prognostic predictors. RBM10 suppresses LUADprogression largely by regulating alternative splicing of EIF4H exon 5. Loss of RBM10 in LUAD enhances the expression of EIF4H-L in LUAD. EIF4H-L , but not EIF4H-S , is critical for LUAD cell proliferation, survival and tumourigenesis. Interpretation Our study demonstrates a new molecular mechanism underlying RBM10 suppressive functions in lung cancer and the therapeutic value of RBM10-regulated AS events, providing important mechanistic and translational insights into splicing defects in cancer.

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“…These activities empowered the recent creation of the International Proteogenome Consortium (ICPC; icpc.cancer.gov) 108 . Collectively, CPTAC and ICPC collaborators have comprehensively characterized 13 cancer types at the proteogenomics level, with all datasets publicly accessible [109][110][111][112][113][114][115][116][117] .…”

Section: Translating Proteomics To Precision Medicinementioning

confidence: 99%

A high-stringency blueprint of the human proteome

et al. 2020

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The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.

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Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression

Cited by 243 publications

References 98 publications

Proteomic Analyses Identify Differentially Expressed Proteins and Pathways Between Low-Risk and High-Risk Subtypes of Early-Stage Lung Adenocarcinoma and Their Prognostic Impacts

Proteomic Analyses Identify Differentially Expressed Proteins and Pathways Between Low-Risk and High-Risk Subtypes of Early-Stage Lung Adenocarcinoma and Their Prognostic Impacts

RNA binding motif protein 10 suppresses lung cancer progression by controlling alternative splicing of eukaryotic translation initiation factor 4H

A high-stringency blueprint of the human proteome

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