Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci

Dai, Juncheng; Li, Zhihua; Amos, Christopher I.; Hung, Rayjean J.; Tardón, Adonina; Andrew, Angeline S.; Chu, Chengcai; Christiani, David C.; Albanes, Demetrios; Heijden, Erik H F M van der; Duell, Eric J.; Rennert, Gad; McKay, James; Yuan, Jian Min; Field, John K.; Manjer, Jonas; Grankvist, Kjell; Marchand, Loı̈c Le; Teare, M. Dawn; Schabath, Matthew B.; Aldrich, Melinda C.; Tsao, Ming‐Sound; Lazarus, Philip; Lam, Stephen; Bojesen, Stig E.; Arnold, Susanne M.; Wu, Xifeng; Haugen, Aage; Janout, Vladimí­r; Johansson, Mikael; Brhane, Yonathan; Fernández-Somoano, Ana; Kiemeney, Lambertus A.; Davies, Michael; Zienolddiny, Shanbeh; Hu, Zhibin; Shen, Hongbing

doi:10.1093/carcin/bgy187

Cited by 7 publications

(8 citation statements)

References 49 publications

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“…The results showed that gene levels of MRGBP were significantly higher in 20 tumors compared to normal tissue. MRGBP expression in colorectal, prostate, and lung cancers is consistent with their previous studies ( Yamaguchi et al, 2010 ; Ito et al, 2018 ; Dai et al, 2019 ) and it was also confirmed by our immunohistochemical results in LGG ( Figure 12A ). These findings suggest that MRGBP may play an important role in the development of the above tumors and it may be a promising diagnostic biomarker in tumors.…”

Section: Discussionsupporting

confidence: 93%

“…When MRGBP is inhibited it induces apoptosis and reduces tumor growth ( Watt et al, 2011 ). Also, it is associated with the progression of lung and cervical cancers ( Scotto et al, 2008 ; Dai et al, 2019 ). MRGBP is involved in a variety of tumor processes, and its expression is significantly increased in a variety of tumors, suggesting that MRGBP may be used as a diagnostic biomarker and therapeutic target for tumors.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic Value and Immunological Role of MORF4-Related Gene-Binding Protein in Human Cancers

Chai

Zhang

Guan

et al. 2021

Front. Cell Dev. Biol.

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MORF4-related gene-binding protein (MRGBP) is the subunit of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. Much of the research indicated an oncogenic role of MRGBP in the development of cancers. However, it is still unknown the role MRGBP plays in human cancers, which deserves further exploration. In this research, the expression profile, prognostic value of MRGBP, and the relationship between MRGBP and immune infiltration were explored in 33 types of cancer. The differences in MRGBP expression in tumor and normal tissues were explored using data from The Cancer Genome Atlas, Gene Expression Omnibus and ONCOMINE. Analysis of the association between MRGBP and prognosis using Kaplan-Meier survival curve and COX analysis. The data of Tumor mutational burden (TMB), microsatellite instability (MSI) from TCGA. The relationship Between MRGBP expression and immunity was analyzed using the ESTIMATE algorithm and CIBERSORT. Furthermore, we explored MRGBP expression and the relationship between MRGBP expression and macrophage infiltration using immunohistochemical analysis in lower grade glioma (LGG). Our results revealed that MRGBP was highly expressed in most cancer tissues compared with normal tissues. Tumors with increased MRGBP expression had a high clinicopathologic stage and poor prognosis. The expression of MRGBP was closely related to the TMB, MSI. We also found a significant negative correlation between MRGBP expression and stromal scores and immune scores in various types of cancer. Furthermore, MRGBP expression was associated with a variety of immune cells including B cells, NK cells, T cells, and macrophages. LGG and LIHC was selected as representative cancer types for further study, the results of immunohistochemistry indicated that the protein levels of MRGBP were significantly elevated in tumor tissues. Moreover, our LIHC data analysis showed that patients with high MRGBP expression were associated with short survival rates and MRGBP was a risk factor to determine OS. Immunohistochemistry also confirmed that M0 macrophage infiltration in the MRGBP-high group significantly increased. In conclusion, these results reveal that MRGBP can serve as a potential prognostic biomarker and it plays an important role in tumor immune infiltration in various tumors, especially in LGG and LIHC.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Prognostic Value and Immunological Role of MORF4-Related Gene-Binding Protein in Human Cancers

Chai

Zhang

Guan

et al. 2021

Front. Cell Dev. Biol.

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“…Furthermore, mutations in DNase I hypersensitive sites (DHS) may alter lung cancer susceptibility by regulating the expression of surrounding genes, a process closely related to MRGBP [ 23 ]. For hepatocellular carcinoma (HCC), the high expression of MRGBP was significantly correlated with tumour T stage, pathological stage, histological grade, vascular invasion, tumour protein P53 status, and overall survival.…”

Section: Discussionmentioning

confidence: 99%

MRGBP: A New Factor for Diagnosis and Prediction of Head and Neck Squamous Cell Carcinoma

Zhao

Wei

Chen

et al. 2022

BioMed Research International

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MRG-binding protein (MRGBP) is a transcription factor widely involved in physiological and pathological processes. Many studies have discussed the relationship between the expression level of MRGBP and the prognosis of various malignant tumours. However, the role and clinicopathological significance of MRGBP in head and neck squamous cell carcinoma (HNSC) are unclear. In this study, the Wilcoxon signed-rank test and logistic regression were used to analyze the relationship between clinical characteristics and MRGBP expression in HNSC. The Kaplan-Meier plotter analysis and Cox regression analysis were established to evaluate the effect of MRGBP on prognosis, and the receiver operating characteristic (ROC) curve and nomogram was constructed. Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were used to analyze the correlation between MRGBP and immune infiltration. The results showed that the expression of MRGBP in HNSC tissues was significantly higher than that in normal tissues. The KM plotter analysis showed that the OS of HNSC patients was shorter. The multivariate Cox analysis further confirmed that increased expression of MRGBP was an independent risk factor for OS in HNSC patients. In addition, ROC analysis confirmed its diagnostic value and constructed prognostic nomograms, including age, T, M, N classification, pathological stage, and MRGBP. GSEA showed that MRGBP was associated with high expression of GPCR ligand binding, interleukin receptor binding, and neutrophil degranulation, and ssGSEA showed that MRGBP was associated with T cells and mast cells. In conclusion, MRGBP can serve as an independent prognostic biomarker related to immune invasion of head and neck squamous cell carcinoma.

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“…The OncoArray dataset was used in the discovery stage with age, gender, and the first three principal components (PCs) adjusted (16). Variations with association P < 0.001 were further tested in the DCEG Lung Cancer Study (the validation stage), and we adjusted age, gender, and the first PC in logistic regression model (23). SNPTEST v2.5 was used for the association analysis, taking dosage format of imputed genotypes.…”

Section: Association Analysismentioning

confidence: 99%

Association Analysis of Driver Gene–Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls

Wang

Gorlova

Gorlov

et al. 2020

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: A substantial proportion of cancer driver genes (CDGs) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. Methods:We selected expression-related single nucleotide polymorphisms (eSNPs) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. Results:We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65×10 -6 ). Subgroup analysis by histological types further identified nine lung CDGs. Analysis of somatic alterations found that, in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76×10 -3 ).Conclusions: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. Impact: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.

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Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci

Cited by 7 publications

References 49 publications

Prognostic Value and Immunological Role of MORF4-Related Gene-Binding Protein in Human Cancers

Prognostic Value and Immunological Role of MORF4-Related Gene-Binding Protein in Human Cancers

MRGBP: A New Factor for Diagnosis and Prediction of Head and Neck Squamous Cell Carcinoma

Association Analysis of Driver Gene–Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls

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