Potential functional variants in SMC2 and TP53 in the AURORA pathway genes and risk of pancreatic cancer

Feng, Yun; Liu, Hongliang; Duan, Bensong; Liu, Zhensheng; Abbruzzese, James L.; Walsh, Kyle M.; Zhang, Xuefeng; Wei, Qingyi

doi:10.1093/carcin/bgz029

Cited by 24 publications

(25 citation statements)

References 58 publications

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“…Although seven SNPs of TP53 (i.e., rs17884306, rs17879377, rs9891744, rs75732100, rs9895829, rs17883323, and rs8079544) located at 17p13 have been previously reported by the AURORA pathway‐based analyses,Query Deleted, the TP53 rs35850753 and other eight SNPs (i.e., MAP2 rs35075084, PRKAG2 rs2727572, rs12668489, rs2538046 and rs34852782 and RPTOR rs62068300, rs17848685 and rs3751936) located at 2q34, 7q36.1, and 17q25.3, respectively, are novel findings, for which we performed additional in silico analysis for their functional relevance. The results of these SNPs in each of GWAS datasets and the final meta‐analysis are summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

Genetic variants in the liver kinase B1‐AMP‐activated protein kinase pathway genes and pancreatic cancer risk

Qian

Liu

et al. 2019

Molecular Carcinogenesis

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The liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) pathway has been identified as a new target for cancer therapy, because it controls the glucose and lipid metabolism in response to alterations in nutrients and intracellular energy levels. In the present study, we aimed to identify genetic variants of the LKB1-AMPK pathway genes and their associations with pancreatic cancer (PanC) risk using 15 418 participants of European ancestry from two previously published PanC genome-wide association studies. We found that six novel tagging single-nucleotide polymorphisms (SNPs) (i.e, MAP2 rs35075084 T > deletion, PRKAG2 rs2727572 C > T and rs34852782 A > deletion, TP53 rs9895829 A > G, and RPTOR rs62068300 G > A and rs3751936 G > C) were significantly associated with an increased PanC risk. The multivariate logistic regression model incorporating the number of unfavorable genotypes (NUGs) with adjustment for age and sex showed that carriers with five to six NUGs had an increased PanC risk (odds ratio = 1.24, 95% confidence interval = 1.16-1.32 and P < 0.0001), compared to those with zero to four NUGs. Subsequent expression quantitative trait loci (eQTL) analysis further revealed that these SNPs were associated with significantly altered mRNA expression levels either in 373 normal lymphoblastoid cell lines (TP53 SNP rs9895829, P < 0.05) or in whole blood cells of 369 normal donors from the genotype-tissue expression project (GTEx) database [RPTOR SNP rs60268947 and rs28434589, both in high linkage disequilibrium (r 2 > 0.9) with RPTOR rs62068300, P < 0.001]. Collectively, our findings suggest that these novel SNPs in the LKB1-AMPK pathway genes may modify susceptibility to PanC, possibly by influencing gene expression. K E Y W O R D S genome-wide association study, pancreatic cancer risk, single-nucleotide polymorphism (SNP) 1 | INTRODUCTION Pancreatic cancer (PanC) is one of the most lethal human malignancies, with an overall 5-year survival rate lower than 10% and a median survival of 6 months, and PanC is also the fourth leading cause of cancer-related death and is expected to become the second within the next decade in the United States. 1,2 The exact cause of PanC is not yet well understood, though several risk Molecular Carcinogenesis. 2019;58:1338-1348. wileyonlinelibrary.com/journal/mc 1338 |

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Section: Resultsmentioning

confidence: 99%

Genetic variants in the liver kinase B1‐AMP‐activated protein kinase pathway genes and pancreatic cancer risk

Qian

Liu

et al. 2019

Molecular Carcinogenesis

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“…By combining a meta-analysis with the largest genome-wide association (GWA) meta-analysis datasets, Kar et al (2016) found that SMC2 is associated with susceptibility to breast and ovarian cancer. Feng et al (2019) used genome-wide association studies (GWASs) of pancreatic cancer datasets and found that the expression level of SMC2 mRNA in human pancreatic cancer tissues was significantly higher than that in adjacent non-neoplastic pancreatic tissues. Davalos et al (2012) found that SMC2 is a direct transcriptional target of the WNT signaling pathway, and experimental results showed that the down-regulation of SMC2 expression can inhibit WNT-activated cell proliferation; therefore, SMC2 could be used as a novel target for therapeutic interventions for tumors.…”

Section: Discussionmentioning

confidence: 99%

Screening and Identification of Therapeutic Targets for Pulmonary Arterial Hypertension Through Microarray Technology

Meng

Liu

2020

Front. Genet.

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Pulmonary arterial hypertension (PAH) is a rare but fatal disease characterized by vascular cell proliferation; the pathogenesis of PAH has yet to be fully elucidated. Publicly available genetic data were downloaded from the Gene Expression Omnibus (GEO) database, and gene set enrichment analysis (GSEA) was used to determine significant differences in gene expression between tissues with PAH and healthy lung tissues. Differentially expressed genes (DEGs) were identified using the online tool, GEO2R, and functional annotation of DEGs was performed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Next, the construction and module analysis of the protein–protein interaction (PPI) network and verification of the expression level of hub genes was performed. Finally, prediction and enrichment analysis of microRNAs associated with the hub genes was carried out. A total of 110 DEGs were detected by screening PAH and healthy lung samples. The expression of nine genes [polo-like kinase 4 (PLK4), centromere protein U, kinesin family member 20B, structural maintenance of chromosome 2 (SMC2), abnormal spindle microtubule assembly, Fanconi Anemia complementation group I, kinesin family member 18A, spindle apparatus coiled-coil protein 1, and MIS18 binding protein 1] was elevated in PAH; this was statistically significant compared with their expression in healthy lung tissue, and they were identified as hub genes. GO and KEGG analysis showed that the variations in DEGs were abundant in DNA-templated transcription, sister chromatid cohesion, mitotic nuclear division, cell proliferation, and regulation of the actin cytoskeleton. In conclusion, this study has successfully identified hub genes and key pathways of PAH, with a total of 110 DEGs and nine hub genes related to PAH, especially the PLK4 and SMC2 genes, thus providing important clues for the in-depth understanding of the molecular mechanism of PAH and providing potential therapeutic targets.

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“…Preliminary clinical studies have been conducted to validate the e cacy and safety of Aurora kinase inhibitors in AML [47][48][49]. Although the association of TP53 mutation and AURKA expression has been rarely studied previously for AML, it was explored in solid tumors with high frequency of TP53 variants, including adrenocortical carcinoma [50], pancreatic cancer [51], head and neck cancer [52], hepatocellular carcinoma [53] and ovarian cancer [54]. Moreover, in cancer cell lines lacking p53, resulting from genetic engineering to express HPV16-E6 oncoprotein or siRNA targeting TP53, the inhibitor of Aurora kinases (VX680) induced apoptosis was enhanced in comparison with cell lines with wide-type p53 [55].…”

Section: Discussionmentioning

confidence: 99%

The Landscape of Gene Co-Expression Modules Correlating with Prognostic Genetic Abnormalities in AML

Guo

Gao

et al. 2020

Preprint

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Background: The heterogenous cytogenetic and molecular variations were harbored by AML patients, some of which are related with AML pathogenesis and clinical outcomes. We aimed to uncover the intrinsic expression profiles correlating with prognostic genetic abnormalities by WGCNA.Methods: We downloaded the clinical and expression dataset from BeatAML, TCGA and GEO database. Using R (version 4.0.2) and ‘WGCNA’ package, the co-expression modules correlating with the ELN2017 prognostic markers were identified (R2 ≥ 0.4, p < 0.01). ORA detected the enriched pathways for the key co-expression modules. The patients in TCGA cohort were randomly assigned into the training set (50%) and testing set (50%). The LASSO penalized regression analysis was employed to build the prediction model, fitting OS to the expression level of hub genes by ‘glmnet’ package. Then the testing and 2 independent validation sets (GSE12417 and GSE37642) were used to validate the diagnostic utility and accuracy of the model. Results: A total of 37 gene co-expression modules and 973 hub genes were identified for the BeatAML cohort. We found that 3 modules were significantly correlated with genetic markers (the ‘lightyellow’ module for NPM1 mutation, the ‘saddlebrown’ module for RUNX1 mutation, the ‘lightgreen’ module for TP53 mutation). ORA revealed that the ‘lightyellow’ module was mainly enriched in DNA-binding transcription factor activity and activation of HOX genes. The ‘saddlebrown’ module was enriched in immune response process. And the ‘lightgreen’ module was predominantly enriched in mitosis cell cycle process. The LASSO- regression analysis identified 6 genes (NFKB2, NEK9, HOXA7, APRC5L, FAM30A and LOC105371592) with non-zero coefficients. The risk score generated from the 6-gene model, was associated with ELN2017 risk stratification, relapsed disease, and prior MDS history. The 5-year AUC for the model was 0.822 and 0.824 in the training and testing sets, respectively. Moreover, the diagnostic utility of the model was robust when it was employed in 2 validation sets (5-year AUC 0.743-0.79).Conclusions: We established the co-expression network signature correlated with the ELN2017 recommended prognostic genetic abnormalities in AML. The 6-gene prediction model for AML survival was developed and validated by multiple datasets.

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Potential functional variants in SMC2 and TP53 in the AURORA pathway genes and risk of pancreatic cancer

Cited by 24 publications

References 58 publications

Genetic variants in the liver kinase B1‐AMP‐activated protein kinase pathway genes and pancreatic cancer risk

Genetic variants in the liver kinase B1‐AMP‐activated protein kinase pathway genes and pancreatic cancer risk

Screening and Identification of Therapeutic Targets for Pulmonary Arterial Hypertension Through Microarray Technology

The Landscape of Gene Co-Expression Modules Correlating with Prognostic Genetic Abnormalities in AML

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