The inherited variations of a p53-responsive enhancer in 13q12.12 confer lung cancer risk by attenuating TNFRSF19 expression

Shao, Lipei; Zuo, Xianglin; Yang, Yonggang; Zhang, Yu; Yang, Nan; Shen, Bin; Wang, Xuchun; Li, Ruilei; Jin, Guangfu; Yu, Debing; Yuan, Chen; Sun, Luan; Li, Zhen; Fu, Qiangqiang; Hu, Zhibin; Han, Xiao; Song, Xin; Shen, Hong‐Bin; Sun, Yujie

doi:10.1186/s13059-019-1696-1

Cited by 31 publications

(14 citation statements)

References 46 publications

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“… 50 Present evidence displayed that TNFRSF19 acted as a tumor suppressor in patients with lung cancer. 51 Although the expression details of these five members in various cancer types have been described, the combination and functions of these molecules still warrants further exploration.…”

Section: Discussionmentioning

confidence: 99%

Identification of a costimulatory molecule-based signature for predicting prognosis risk and immunotherapy response in patients with lung adenocarcinoma

Zhang

Sun

et al. 2020

OncoImmunology

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Background: Costimulatory molecules play significant roles in mounting anti-tumor immune responses, and antibodies targeting these molecules are recognized as promising adjunctive cancer immunotherapies. Here, we aim to conduct a first full-scale exploration of costimulatory molecules from the B7-CD28 and TNF families in patients with lung adenocarcinoma (LUAD) and generated a costimulatory moleculebased signature (CMS) to predict survival and response to immunotherapy. Methods: We enrolled 1549 LUAD cases across 10 different cohorts and included 502 samples from TCGA for discovery. The validation set included 970 cases from eight different Gene Expression Omnibus (GEO) datasets and 77 frozen tumor tissues with qPCR data. The underlying mechanisms and predictive immunotherapy capabilities of the CMS were also explored. Results: A five gene-based CMS (CD40LG, TNFRSF6B, TNFSF13, TNFRSF13C, and TNFRSF19) was initially constructed using the bioinformatics method from TCGA that classifies cases as high-vs. low-risk groups per OS. Multivariable Cox regression analysis confirmed that the CMS was an independent prognostic factor. As expected, CMS exhibited prognostic significance in the stratified cohorts and different validation cohorts. Additionally, the prognostic meta-analysis revealed that CMS was superior to the previous signature. Samples in high-and low-risk groups exhibited significantly different tumor-infiltrating leukocytes and inflammatory activities. Importantly, we found that the CMS scores were closely related to multiple immunotherapy biomarkers. Conclusion: We conducted the first and most comprehensive costimulatory molecule landscape analysis of patients with LUAD and built a clinically feasible CMS for prognosis and immunotherapy response prediction, which will be helpful for further optimize immunotherapies for cancer.

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Section: Discussionmentioning

confidence: 99%

Identification of a costimulatory molecule-based signature for predicting prognosis risk and immunotherapy response in patients with lung adenocarcinoma

Zhang

Sun

et al. 2020

OncoImmunology

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“…acted as a tumor suppressor in patients with lung cancer. [51] Although the expression details of these five members in various cancer types have been described, the combination and functions of these molecules still warrants further exploration.…”

Section: Discussionmentioning

confidence: 99%

Identification of a costimulatory molecule-based signature for predicting prognosis risk and immunotherapy response in patients with lung adenocarcinoma

Zhang

Sun

et al. 2020

Preprint

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Background Costimulatory molecules play significant roles in mounting anti-tumor immune responses, and antibodies targeting these molecules are recognized as promising adjunctive cancer immunotherapies. Here, we aim to conduct a first full-scale exploration of costimulatory molecules from the B7-CD28 and TNF families in patients with lung adenocarcinoma (LUAD) and generated a costimulatory molecule-based signature (CMS) to predict survival and response to immunotherapy. Methods We enrolled 1549 LUAD cases across 10 different cohorts and included 502 samples from TCGA for discovery. The validation set included 970 cases from eight different Gene Expression Omnibus (GEO) datasets and 77 frozen tumor tissues with qPCR data. The underlying mechanisms and predictive immunotherapy capabilities of the CMS were also explored. Results A five gene-based CMS (CD40LG, TNFRSF6B, TNFSF13, TNFRSF13C, and TNFRSF19) was initially constructed using the bioinformatics method from TCGA that classifies cases as high- vs. low-risk groups per OS. Multivariable Cox regression analysis confirmed that the CMS was an independent prognostic factor. As expected, CMS exhibited prognostic significance in the stratified cohorts and different validation cohorts. Additionally, the prognostic meta-analysis revealed that CMS was superior to the previous signature. Samples in high- and low-risk groups exhibited significantly different tumor-infiltrating leukocytes and inflammatory activities. Importantly, we found that signature high-risk patients were optimal candidates for immunotherapy. Conclusion We conducted the first and most comprehensive costimulatory molecule landscape analysis of patients with LUAD and built a clinically feasible CMS for prognosis and immunotherapy response prediction, which will be helpful for further optimize immunotherapies for cancer.

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“…A recent in vivo CRISPR/Cas9-screening approach identified CEBPB binding within a p53dependent CRE required for optimal transcription of CDKN1A and initiation of senescence (22). Single nucleotide polymorphisms associated with lung cancer risk found within a p53-regulated CRE disrupt canonical transcription factor motifs, reduce p53 binding, and alter expression of TNFRSF19 (7). In this study, we identified both ATF3 and a likely member of the SP1/KLF family as co-regulatory transcription factors required for p53-dependent CRE activity.…”

Section: The Requirement For Other Transcription Factors Co-regulatinmentioning

confidence: 99%

Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

Catizone

Uzunbas

Celadova

et al. 2019

Preprint

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The master tumor suppressor p53 controls transcription of a wide-ranging gene network involved in apoptosis, cell cycle arrest, DNA damage repair, and senescence. Recent studies revealed pervasive binding of p53 to cis-regulatory elements (CRE), which are non-coding segments of DNA that spatially and temporally control transcription through the combinatorial binding of local transcription factors (TFs). Although the role of p53 as a strong trans-activator of gene expression is well known, the coregulatory factors and local sequences acting at p53-bound CREs are comparatively understudied. We designed and executed a massively parallel reporter assay (MPRA) to investigate the effect of transcription factor binding motifs and local sequence context on p53-bound CRE activity. Our data indicate that p53-bound CREs are both positively and negatively affected by alterations in local sequence context and changes to co-regulatory TF motifs. We identified a SP1/KLF family motif located in an intronic p53 CRE that is required for the endogenous expression of the p53-dependent gene CCNG1. We also identified ATF3 as a factor that co-regulates the expression of the p53-dependent gene GDF15 through binding with p53 in an upstream CRE. Loss of either p53 or ATF3 severely reduces CRE activity and alters endogenous GDF15 mRNA levels in the cell. Our data suggests that p53 has the flexibility to cooperate with a variety of transcription factors in order to regulate CRE activity. By utilizing different sets of co-factors across CREs, we hypothesize that p53 activity is guarded against loss of any one regulatory partner allowing for dynamic and redundant control of p53mediated transcription.Recent evidence suggests that sequence variation within cis-regulatory elements (CREs) can influence p53 binding, transcriptional activity, and tumor suppressor function (5-7) . The critical nature of the core p53 response element (p53RE) on p53 binding and CRE activity is well understood (8-10), but the influence of local sequence variation and the role of transcription factor motifs outside of the p53RE on p53 activity remains an open and vital question.Cis-regulatory elements, such as promoters and enhancers, govern gene expression through temporal, spatial, and quantitative control of transcription (11,12). While multiple models for CRE function have been proposed, the majority involve cooperative binding and activity of multiple transcription factors and cofactors acting locally to fine-tune gene expression (11)(12)(13). The presence and availability of transcription factors, repressors, and other cofactors vary across cell states such as development, stress, disease, and cell type (14-17). This variability provides a mechanism for differential CRE activity and downstream gene expression. Loss of transcription factor binding within a CRE, through variation in DNA sequence or through changes in trans-factor availability, can strongly influence CRE activity and gene expression (11,12,18), with direct implications in numerous developmental and d...

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The inherited variations of a p53-responsive enhancer in 13q12.12 confer lung cancer risk by attenuating TNFRSF19 expression

Cited by 31 publications

References 46 publications

Identification of a costimulatory molecule-based signature for predicting prognosis risk and immunotherapy response in patients with lung adenocarcinoma

Identification of a costimulatory molecule-based signature for predicting prognosis risk and immunotherapy response in patients with lung adenocarcinoma

Identification of a costimulatory molecule-based signature for predicting prognosis risk and immunotherapy response in patients with lung adenocarcinoma

Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

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