Genomic and immune profiling of pre-invasive lung adenocarcinoma

Chen, Haiquan; Carrot-Zhang, Jian; Zhao, Yue; Hu, Haichuan; Freeman, Samuel S.; Yu, Su Jeong; Ha, Gavin; Taylor, Alison M.; Berger, Ashton C.; Westlake, Lindsay; Zheng, Yuanting; Zhang, Jiyang; Ramachandran, Aruna; Zheng, Qiang; Pan, Yunjian; Zheng, Deyou; Zheng, Shanbo; Cheng, Chao; Kuang, Muyu; Zhou, Xiaoyan; Zhang, Yang; Li, Hang; Ye, Ting; Ma, Yuan; Gao, Zhendong; Tao, Xiaoting; Han, Han; Shang, Jun; Yu, Ying; Bao, Ding; Huang, Yechao; Li, Xiangnan; Zhang, Yawei; Xiang, Jiaqing; Sun, Yihua; Li, Yuan; Cherniack, Andrew D.; Campbell, Joshua D.; Shi, Leming; Meyerson, Matthew

doi:10.1038/s41467-019-13460-3

Cited by 158 publications

(158 citation statements)

References 35 publications

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“…The RBM10 mutation frequency is ~8% in The Cancer Genome Atlas (TCGA) LUAD patients [ 27 , 28 ], but is less well-defined in other populations with distinct oncogenic mutational spectrums [29] . Notably, RBM10 mutations have been shown to be enriched [30] and clonal in early stage LUADs [31] , suggesting a role in driving the development of LUAD. The analyses of LUAD samples in TCGA indicate that RBM10 mutations may contribute to LUAD progression [32] and associate with a number of splicing changes [33] .…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…In our previous study, we performed RNA‐seq in 197 patients . We selected sequencing data of seven patients with BM and 45 patients without BM.…”

Section: Resultsmentioning

confidence: 99%

Development and validation of a five‐gene model to predict postoperative brain metastasis in operable lung adenocarcinoma

Zhang

Gao

et al. 2020

Intl Journal of Cancer

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One of the most common sites of extra-thoracic distant metastasis of nonsmall-cell lung cancer is the brain. Our study was performed to discover genes associated with postoperative brain metastasis in operable lung adenocarcinoma (LUAD). RNA seq was performed in specimens of primary LUAD from seven patients with brain metastases and 45 patients without recurrence. Immunohistochemical (IHC) assays of the differentially expressed genes were conducted in 272 surgical-resected LUAD specimens. LASSO Cox regression was used to filter genes related to brain metastasis and construct brain metastasis score (BMS). GSE31210 and GSE50081 were used as validation datasets of the model. Gene Set Enrichment Analysis was performed in patients stratified by risk of brain metastasis in the TCGA database. Through the initial screening, eight genes (CDK1, KPNA2, KIF11, ASPM, CEP55, HJURP, TYMS and TTK) were selected for IHC analyses. The BMS based on protein expression levels of five genes (TYMS, CDK1, HJURP, CEP55 and KIF11) was highly predictive of brain metastasis in our cohort (12-month AUC: 0.791, 36-month AUC: 0.766, 60-month AUC: 0.812). The validation of BMS on overall survival of GSE31210 and GSE50081 also showed excellent predictive value (GSE31210, 12-month AUC: 0.682, 36-month AUC: 0.713, 60-month AUC: 0.762; GSE50081, 12-month AUC: 0.706, 36-month AUC: 0.700, 60-month AUC: 0.724). Further analyses showed high BMS was associated with pathways of cell cycle and DNA repair. A five-gene predictive model exhibits potential clinical utility for the prediction of postoperative brain metastasis and the individual management of patients with LUAD after radical resection.F.F. and Y.Z. contributed equally to this work. Additional Supporting Information may be found in the online version of this article.

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“…Cancer evolution is shaped by interaction between cancer cells and host factors, particularly the host immune response. Given T cells' central role in anti-tumor immune surveillance 24,43 , we depicted the T cell infiltration in AIS, MIA and invasive ADC by deconvoluting RNA sequencing data from an independent dataset recently published 44 .…”

Section: Global Hypomethylation Was Associated With Suppressed T Cellmentioning

confidence: 99%

Evolution of DNA methylome from precancer to invasive lung adenocarcinoma

Estécio

Chen

et al. 2020

Preprint

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The evolution of DNA methylation at genome level and methylation intra-tumor heterogeneity (ITH) during early lung carcinogenesis has not been systematically studied. We performed multiregional reduced representation bisulfite sequencing (RRBS) of 62 resected lung nodules from 39 patients including atypical adenomatous hyperplasia (AAH, n=14), adenocarcinoma in situ (AIS, n=15), minimally invasive adenocarcinoma (MIA, n=22), and invasive adenocarcinoma (ADC, n=11). We observed significantly higher level of methylation ITH in later-stage lesions and gradual increase in both hyper- and hypomethylation compared to matched normal lung tissues over the course of neoplastic progression. The phyloepigenetic patterns inferred from methylation aberrations resembled those based on somatic mutations suggesting parallel methylation and genetic evolution during the early lung carcinogenesis. De-convolution of transcriptomic profiles from a previously published cohort and RBBS data from the current cohort demonstrated higher ratios of T regulatory cells (Tregs) versus CD8+ T cells in later-stage diseases implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation was associated with higher mutation burden, higher copy number aberration burden, higher allelic imbalance burden as well as higher Treg/CD8 ratio highlighting the potential impact of methylation states on chromosomal instability, mutagenesis and the tumor immune microenvironment.

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Genomic and immune profiling of pre-invasive lung adenocarcinoma

Cited by 158 publications

References 35 publications

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

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

Development and validation of a five‐gene model to predict postoperative brain metastasis in operable lung adenocarcinoma

Evolution of DNA methylome from precancer to invasive lung adenocarcinoma

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