Dataset Information

A Propensity Score-adjusted Analysis of the Effects of Ubiquitin E3 Ligase Copy Number Variation in Peripheral Blood Leukocytes on Colorectal Cancer Risk.

ABSTRACT: Background: The ubiquitin ligases E3 (E3s) plays a key role in the specific protein degradation in many carcinogenic biological processes. Colorectal cancer (CRC) development may be affected by the copy number variation (CNV) of E3s. Prior studies may have underestimated the impact of potential confounding factors' effects on the association between gene CNV and CRC risk, and CRC risk predictive model integrating gene CNV patterns is lacking. Our research sought to assess the genes CNVs of MDM2, SKP2, FBXW7, ?-TRCP, and NEDD4-1 and CRC risk by using propensity score (PS) adjustment and developing models that integrate CNV patterns for CRC risk predictions. Methods: This study comprising 1036 participants used traditional regression and different PS techniques to adjust the confounding factors to evaluate the relationships between five gene CNVs and CRC risk, and to establish a CRC risk predictive model. The AUC was applied to evaluate the effect of the model. The categorical net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) were analyzed to evaluate the discriminatory accuracy improvement among the models. Results: Compared to variable adjustment, the odds ratios (ORs) tended to be conservative and accurate with narrow confidence intervals (CIs) after PS adjustment. After PS adjustment, MDM2 amplification was related to increased CRC risk (Amp-pattern: OR = 8.684, 95% CI: 1.213-62.155, P = 0.031), whereas SKP2 deletion and the (del+amp) genotype were associated with reduced CRC risk (Del-pattern: OR = 0.323, 95% CI: 0.106-0.979, P = 0.046; Var-pattern: OR = 0.339, 95% CI: 0.135-0.854, P = 0.024). The predictive model integrating the gene CNV pattern could correctly reclassify 1.7% of the subjects. Conclusions: MDM2 amplification and SKP2 CNVs are associated with increased and decreased CRC risk, respectively; abnormal CNV-integrated model is more precise for predicting CRC risk. Further studies are needed to verify these encouraging outcomes.

SUBMITTER: Bi H

PROVIDER: S-EPMC6603381 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Propensity Score-adjusted Analysis of the Effects of Ubiquitin E3 Ligase Copy Number Variation in Peripheral Blood Leukocytes on Colorectal Cancer Risk.

Bi Haoran H Liu Yupeng Y Tian Tian T Xia Tingting T Pu Rui R Zhang Yiwei Y Hu Fulan F Zhao Yashuang Y

Journal of Cancer 20190602 14

<b>Background</b>: The ubiquitin ligases E3 (E3s) plays a key role in the specific protein degradation in many carcinogenic biological processes. Colorectal cancer (CRC) development may be affected by the copy number variation (CNV) of E3s. Prior studies may have underestimated the impact of potential confounding factors' effects on the association between gene CNV and CRC risk, and CRC risk predictive model integrating gene CNV patterns is lacking. Our research sought to assess the genes CNVs o ...[more]

PMID: 31289601

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Project description:The PINK1 (phosphatase and tensin homologue-induced putative kinase 1)/Parkin-dependent mitochondrial quality control pathway mediates the clearance of damaged organelles, but appears to be disrupted in Parkinson's disease (PD) [Springer and Kahle (2011) Autophagy 7, 266-278]. Upon mitochondrial stress, PINK1 activates the E3 ubiquitin (Ub) ligase Parkin through phosphorylation of the Ub-like (UBL) domain of Parkin and of the small modifier Ub itself at a conserved residue [Sauvé and Gehring (2014) Cell Res. 24, 1025-1026]. Recently resolved partial crystal structures of Parkin showed a 'closed', auto-inhibited conformation, consistent with its notoriously weak enzymatic activity at steady state [Wauer and Komander (2013) EMBO J. 32, 2099-2112; Riley et al. (2013) Nat. Commun. 4, 1982; Trempe et al. (2013) Science 340, 1451-1455; Spratt et al. (2013) Nat. Commun. 4, 1983]. It has thus become clear that Parkin must undergo major structural rearrangements in order to unleash its catalytic functions. Recent published findings derived from X-ray structures and molecular modelling present a complete structural model of human Parkin at an all-atom resolution [Caulfield et al. (2014) PLoS Comput. Biol. 10, e1003935]. The results of the combined in silico simulations-based and experimental assay-based study indicates that PINK1-dependent Ser65 phosphorylation of Parkin is required for its activation and triggering of 'opening' conformations. Indeed, the obtained structures showed a sequential release of Parkin's intertwined domains and allowed docking of an Ub-charged E2 coenzyme, which could enable its enzymatic activity. In addition, using cell-based screening, select E2 enzymes that redundantly, cooperatively or antagonistically regulate Parkin's activation and/or enzymatic functions at different stages of the mitochondrial autophagy (mitophagy) process were identified [Fiesel et al. (2014) J. Cell Sci. 127, 3488-3504]. Other work that aims to pin-point the particular pathogenic dysfunctions of Parkin mis-sense mutations have been recently disseminated (Fabienne C. Fiesel, Thomas R. Caulfield, Elisabeth L. Moussaud-Lamodiere, Daniel F.A.R. Dourado, Kotaro Ogaki, Owen A. Ross, Samuel C. Flores, and Wolfdieter Springer, submitted). Such a structure-function approach provides the basis for the dissection of Parkin's regulation and a targeted drug design to identify small-molecule activators of this neuroprotective E3 Ub ligase.

Dataset Information

A Propensity Score-adjusted Analysis of the Effects of Ubiquitin E3 Ligase Copy Number Variation in Peripheral Blood Leukocytes on Colorectal Cancer Risk.

Publications

A Propensity Score-adjusted Analysis of the Effects of Ubiquitin E3 Ligase Copy Number Variation in Peripheral Blood Leukocytes on Colorectal Cancer Risk.

Similar Datasets

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