PRKDC regulates chemosensitivity and is a potential prognostic and predictive marker of response to adjuvant chemotherapy in breast cancer patients

Sun, Gang; Liu, Yang; Dong, Chao; Ma, Baochun; Shan, Meihui; Ma, Binlin

doi:10.3892/or.2017.5634

Cited by 40 publications

(31 citation statements)

References 32 publications

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“…According to recent studies, gene CCNB1 is a prognostic biomarker for certain subtypes of breast cancer and it is closely associated with hormone therapy resistance [20]. It has also been reported in the literature that the PRKDC regulates chemosensitivity and is a potential prognostic and predictive marker of response to adjuvant chemotherapy in breast cancer patients [21]. Our findings about several other genes including CHEK2 and CDC7 also confirmed some existing reports [22,23].…”

Section: A Genomic Applicationsupporting

confidence: 89%

Testing Differential Gene Networks under Nonparanormal Graphical Models with False Discovery Rate Control

Zhang¹

2020

Genes

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The nonparanormal graphical model has emerged as an important tool for modeling dependency structure between variables because it is flexible to non-Gaussian data while maintaining the good interpretability and computational convenience of Gaussian graphical models. In this paper, we consider the problem of detecting differential substructure between two nonparanormal graphical models with false discovery rate control. We construct a new statistic based on a truncated estimator of the unknown transformation functions, together with a bias-corrected sample covariance. Furthermore, we show that the new test statistic converges to the same distribution as its oracle counterpart does. Both synthetic data and real cancer genomic data are used to illustrate the promise of the new method. Our proposed testing framework is simple and scalable, facilitating its applications to large-scale data. The computational pipeline has been implemented in the R package DNetFinder, which is freely available through the Comprehensive R Archive Network.

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Section: A Genomic Applicationsupporting

confidence: 89%

Testing Differential Gene Networks under Nonparanormal Graphical Models with False Discovery Rate Control

Zhang¹

2020

Genes

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“…Similar to the gene mutation profile, HR and NHEJ had a significant gene amplification profile. Previous studies demonstrated that DSB repair pathway genes were over-expressed in cancers and high expression of these genes was associated with cancer development and resistance to chemotherapy and radiotherapy (8,10,11,25,26,47,48). However, how altered DSB repair pathways contribute to ESCC is much less explored.…”

Section: Discussionmentioning

confidence: 99%

“…Up-regulation of DDR pathways are linked to cause resistance to DNA-damaging radiotherapy and chemotherapy. Especially, activation of DSB repair genes is one of the reasons for cancer radio-and chemo-resistance (4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Analysis of Alterations in DNA Damage Repair Pathways Reveals a Potential Way to Enhance the Radio-Sensitivity of Esophageal Squamous Cell Cancer

et al. 2020

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Esophageal squamous cell cancer (ESCC) is a common malignancy with a poor 5-year overall survival in China. Altered DNA damage repair (DDR) pathways are associated with a predisposition to cancer and contribute to therapeutic response and resistance in cancers. However, alterations of DDR pathway genes in ESCC are still largely unknown. In this study, we employed genome sequencing data of 192 samples, comparative genomic hybridization data of 123 cases, and gene expression microarray data of 119 patients to firstly perform a comprehensive analysis of the gene alterations of 7 DDR pathways in ESCC. Gene mutations and copy number variations (CNVs) were observed in all 7 DDR pathways, and especially, CNVs were the dominant alteration types. Compared with other pathways, two DNA double-strand break (DSB) repair pathways homologous recombination (HR) and nonhomologous end joining (NHEJ), carried significant gene mutations and CNVs especially gene amplifications. Most genes including RAD54B, NBS1, RAD51B, and PRKDC were significantly amplified and over-expressed in ESCC. Amplification and high expression of DSB repair pathway genes were associated with poorer overall survival. Gene set variation analysis further showed that DSB repair pathways were up-regulated in ESCC. Besides, we firstly demonstrated that combination of mirin and NU7441, two inhibitors for HR and NHEJ respectively, with ionizing radiation treatment significantly enhanced DSBs, reduced clonogenic cell survival, inhibited cell proliferation, and promoted cell apoptosis in ESCC cells with DSB pathway gene amplification. These findings suggest that DSB repair pathways were significantly altered in ESCC and inhibiting DSB repair pathways might enhance the radio-sensitivity of ESCC with DSB repair up-regulation.

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“…For RNA-seq data for the TMZ-sensitive LN229 cells ( Figure 5 ), when comparing combined TMZ + OKN to UT treatments ( Figure 5 A ), an interesting downregulated gene includes PODXL (a marker for gastric cancer [53] ), and interesting upregulated genes include TRIB3 (induces apoptosis and reverses resistance to chemotherapy in hepatic carcinoma cells [54] ) and CHAC1 (enhances glioma apoptosis [55] ). When comparing combined TMZ + OKN treatment to TMZ alone ( Figure 5 B ), interesting downregulated genes are IGR1 (associated with shorter disease-free survival in patients whose tumors are ER positive and HER2 positive [56] ; IGF1R signaling pathway is very relevant in drug resistance [57] ), XIST (increased level associated with shorter survival and poorer prognosis [58] ), and PRKDC (prognostic biomarker for chemoresistance in breast cancer patients [59] ). Interesting upregulated genes include ZC3H12A (crucial negative regulator of inflammation [60] ) and RN7SK (potential antiproliferative and tumor-suppressive function [61] ).…”

Section: Discussionmentioning

confidence: 99%

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

Towner

Smith

Saunders

et al. 2019

Translational Oncology

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Treatment of glioblastoma (GBM) remains a challenge using conventional chemotherapy, such as temozolomide (TMZ), and is often ineffective as a result of drug resistance. We have assessed a novel nitrone-based agent, OKN-007, and found it to be effective in decreasing tumor volumes and increasing survival in orthotopic GBM xenografts by decreasing cell proliferation and angiogenesis and increasing apoptosis. In this study, we assessed combining OKN-007 with TMZ in vivo in a human G55 GBM orthotopic xenograft model and in vitro in TMZ-resistant and TMZ-sensitive human GBM cell lines. For the in vivo studies, magnetic resonance imaging was used to assess tumor growth and vascular alterations. Percent animal survival was also determined. For the in vitro studies, cell growth, IC50 values, RNA-seq, RT-PCR, and ELISA were used to assess growth inhibition, possible mechanism-of actions (MOAs) associated with combined OKN-007 + TMZ versus TMZ alone, and gene and protein expression levels, respectively. Microarray analysis of OKN-007–treated rat F98 glioma tumors was also carried out to determine possible MOAs of OKN-007 in glioma-bearing animals either treated or not treated with OKN-007. OKN-007 seems to elicit its effect on GBM tumors via inhibition of tumorigenic TGF-β1, which affects the extracellular matrix. When combined with TMZ, OKN-007 significantly increases percent survival, decreases tumor volumes, and normalizes tumor blood vasculature in vivo compared to untreated tumors and seems to affect TMZ-resistant GBM cells possibly via IDO-1, SUMO2, and PFN1 in vitro. Combined OKN-007 + TMZ may be a potentially potent treatment strategy for GBM patients.

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PRKDC regulates chemosensitivity and is a potential prognostic and predictive marker of response to adjuvant chemotherapy in breast cancer patients

Cited by 40 publications

References 32 publications

Testing Differential Gene Networks under Nonparanormal Graphical Models with False Discovery Rate Control

Testing Differential Gene Networks under Nonparanormal Graphical Models with False Discovery Rate Control

A Comprehensive Analysis of Alterations in DNA Damage Repair Pathways Reveals a Potential Way to Enhance the Radio-Sensitivity of Esophageal Squamous Cell Cancer

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

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