Integrative pharmacogenomics revealed three subtypes with different immune landscapes and specific therapeutic responses in lung adenocarcinoma

Ge, Xiaoyong; Weng, Siyuan; Xu, Hui; Zhang, Yuyuan; Liu, Long; Dang, Qin; Guo, Chunguang; Beatson, Richard; Deng, Jinhai; Han, Xinwei

doi:10.1016/j.csbj.2022.06.064

Cited by 4 publications

(4 citation statements)

References 38 publications

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“…In this regard, our results showed that AD2, despite having high TMB was an immune cold subtype, and was 80% less likely to respond to immunotherapy than tumors classified in other subtypes. This result is concordant with the findings of a previous study that also identified a LUAD subtype with high TMB but no apparent immune infiltration [ 35 ]. Overall, these results underline the limitation of TMB to predict potential response to immunotherapy in LUAD [ 42 ].…”

Section: Discussionsupporting

confidence: 93%

“…Since early 2000s, there have been several efforts to define clinically relevant LUAD transcriptional subtypes, which resulted in various different classifications [ 8 , 30 , 35 , 36 ]. Despite all these studies, LUAD subtypes have never been translated into the clinical setting.…”

Section: Discussionmentioning

confidence: 99%

“…We tried to overcome this limitation by integrating drug sensitivity data from in vitro pharmacogenomics studies [ 31 ]. These databases have greater drug coverage compared with other available ones such as CMap, which has been used for similar purposes [ 35 ]. Although significant discrepancies can exist between drug response results obtained from cancer cell lines and clinical response in patients, we were able to identify some potential drug candidates for the different LUAD subtypes, in line with their molecular characteristics.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional analysis of landmark molecular pathways in lung adenocarcinoma results in a clinically relevant classification with potential therapeutic implications

Hijazo‐Pechero,

Alay,

Cordero

et al. 2023

Molecular Oncology

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Lung adenocarcinoma (LUAD) is a molecularly heterogeneous disease. In addition to genomic alterations, cancer transcriptional profiling can be helpful to tailor cancer treatment and to estimate each patient's outcome. Transcriptional activity levels of 50 molecular pathways were inferred in 4,573 LUAD patients using Gene Set Variation Analysis (GSVA) method. Seven LUAD subtypes were defined and independently validated based on the combined behavior of the studied pathways: AD (adenocarcinoma subtype)1‐7. AD1, AD4 and AD5 subtypes were associated with better overall survival. AD1 and AD4 subtypes were enriched in epidermal growth factor receptor (EGFR) mutations, whereas AD2 and AD6 showed higher tumor protein p53 (TP53) alteration frequencies. AD2 and AD6 subtypes correlated with higher genome instability, proliferation‐related pathways expression and specific sensitivity to chemotherapy, based on data from LUAD cell lines. LUAD subtypes were able to predict immunotherapy response in addition to CD274 (PD‐L1) gene expression and tumor mutational burden (TMB). AD2 and AD4 subtypes were associated with potential resistance and response to immunotherapy, respectively. Thus, analysis of transcriptomic data could improve patient stratification beyond genomics and single biomarkers (i.e., PD‐L1, TMB) and may lay the foundation for more personalized treatment avenues, especially in driver‐negative LUAD.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Transcriptional analysis of landmark molecular pathways in lung adenocarcinoma results in a clinically relevant classification with potential therapeutic implications

Hijazo‐Pechero,

Alay,

Cordero

et al. 2023

Molecular Oncology

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“…Whole genome sequencing data have revealed that the initiation and progression of LUAD is driven by the most highly somatic mutations in a diverse set of oncogenes, such as TP53, KRAS, EGFR, BRAF and MET 1 12 13. Each of the oncogenic mutations and/or combination of part of these driver mutations promoted tumourigenesis to result in different LUAD subtypes 14 15. The accumulation of diverse mutations in malignant cells then contributed to the heterogeneity of tumours.…”

Section: Introductionmentioning

confidence: 99%

Single-cell RNA-sequencing uncovers the dynamic changes of tumour immune microenvironment in advanced lung adenocarcinoma

Lu,

Qian,

Cheng

et al. 2023

BMJ Open Resp Res

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BackgroundThe heterogeneity of lung adenocarcinoma (LUAD) plays a vital role in determining the development of cancer and therapeutic sensitivity and significantly hinders the clinical treatment of LUAD.ObjectiveTo elucidate the cellular composition and reveal previously uncharacterised tumour microenvironment in LUAD using single-cell RNA-sequencing (scRNA-seq).MethodsTwo scRNA-seq datasets with 106 829 high-quality cells from 34 patients including 11 normal, 9 early (stage I and II) and 14 advanced (stage III and IV) LUAD were integrated and clustered to explore diagnostic and therapeutic cell populations and their biomarkers for diverse stages of LUAD. Three independent bulk RNA-seq datasets were used to validate the results from scRNA-seq analysis. The expression of marker genes for specific cell types in early and advanced LUAD was verified by immunohistochemistry (IHC).ResultsComprehensive cluster analysis identified that S100P+ epithelial and SPP1+ macrophage, positively related to poor outcomes, were preferentially enriched in advanced stage. Although the accumulation of KLRB1+CD8+ T cell and IGHA1+/IGHG1+ plasma cell both significantly associated the favourable prognosis, we also found KLRB1+CD8+ T cell decreased in advanced stage while IGHA1+/IGHG1+ plasma cells were increased. Cell-cell communication analysis showed that SPP1+ macrophage could interact with most of CD8+ subclusters through SPP1-CD44 axis. Furthermore, based on three independent bulk RNA-seq datasets, we built risk model with nine marker genes for specific cell subtypes and conducted deconvolution analysis, both supporting our results from scRNA-seq data. We finally validated the expression of four marker genes in early and advanced LUAD by IHC.ConclusionOur analyses highlight the molecular dynamics of LUAD epithelial and microenvironment and provide new targets to improve LUAD therapy.

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Genome-scale CRISPR-Cas9 screening stratifies pancreatic cancer with distinct outcomes and immunotherapeutic efficacy

Wang

Weng

et al. 2023

Cellular Signalling

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Integrative pharmacogenomics revealed three subtypes with different immune landscapes and specific therapeutic responses in lung adenocarcinoma

Cited by 4 publications

References 38 publications

Transcriptional analysis of landmark molecular pathways in lung adenocarcinoma results in a clinically relevant classification with potential therapeutic implications

Transcriptional analysis of landmark molecular pathways in lung adenocarcinoma results in a clinically relevant classification with potential therapeutic implications

Single-cell RNA-sequencing uncovers the dynamic changes of tumour immune microenvironment in advanced lung adenocarcinoma

Genome-scale CRISPR-Cas9 screening stratifies pancreatic cancer with distinct outcomes and immunotherapeutic efficacy

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