81 results on '"Xin-Ran Tang"'
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2. Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies—pharmacovigilance database analysis with real-world data validation
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Xue-Jun Guo, Xiao-Ting Cai, Zi-Xuan Rong, Yan-Pei Zhang, Yu-Xiang Wen, Xue Bai, Jian Wang, Qiang John Fu, Ze-Qin Guo, Li-Li Long, Si-Cong Ma, Xin-Ran Tang, Li Liu, Jian Guan, Zhong-Yi Dong, and De-Hua Wu
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Interstitial pneumonitis ,Non-small cell lung cancer ,Immune checkpoint inhibitors ,Radiation therapy ,Conventional therapy ,Medicine - Abstract
Abstract Background Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. Methods A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. Results Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05–8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60–184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78–1.04; P = 0.160) and 1.49 (95% CI, 0.95–2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34–50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89–7.92; P = 0.12) and 0.66 (95% CI, 0.03–4.55; P = 0.71), respectively, using ICI monotherapy as reference. Conclusions Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.
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- 2023
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3. Correction to: YPEL3 suppresses epithelial–mesenchymal transition and metastasis of nasopharyngeal carcinoma cells through the Wnt/β-catenin signaling pathway
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Jian Zhang, Xin Wen, Xian-Yue Ren, Ying-Qin Li, Xin-Ran Tang, Ya-Qin Wang, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Na Liu, and Jun Ma
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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4. Corrigendum to 'NFAT1 hypermethylation promotes epithelial‐mesenchymal transition and metastasis in nasopharyngeal carcinoma by activating ITGA6 transcription' [Neoplasia 21 (2019): 311–321]
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Jian Zhang, Zi-Qi Zheng, Ya-Wei Yuan, Pan-Pan Zhang, Ying-Qin Li, Ya-Qin Wang, Xin-Ran Tang, Xin Wen, Xiao-Hong Hong, Yuan Lei, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Jun Ma, and Na Liu
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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5. Correction to: YPEL3 suppresses epithelial–mesenchymal transition and metastasis of nasopharyngeal carcinoma cells through the Wnt/β-catenin signaling pathway
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Jian Zhang, Xin Wen, Xian-Yue Ren, Ying-Qin Li, Xin-Ran Tang, Ya-Qin Wang, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Na Liu, and Jun Ma
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
An amendment to this paper has been published and can be accessed via the original article.
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- 2020
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6. Comprehensive Characterization of Immune Landscape Based on Epithelial-Mesenchymal Transition Signature in OSCC: Implication for Prognosis and Immunotherapy
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Si-yuan Zhang, Xian-yue Ren, Chun-yang Wang, Xi-juan Chen, Ruo-yan Cao, Qin Liu, Xue Pan, Jia-ying Zhou, Wei-lin Zhang, Xin-Ran Tang, Bin Cheng, and Tong Wu
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oral squamous cell carcinoma ,epithelial to mesenchymal transition ,tumor microenvironment ,prognosis ,immune checkpoint ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Current anatomic TNM stage classification fails to capture the immune heterogeneity of oral squamous cell carcinoma (OSCC). Increasing evidence indicates the strong association between epithelial-mesenchymal transition (EMT) and tumor immune response. In this study, we employed an EMT signature to classify OSCC patients into epithelial- (E-) and mesenchymal- (M-) phenotypes using TCGA and GSE41613 transcriptome data. The ESTIMATE and CIRBERSORT analyses implied that the EMT signature genes originated from the stroma of the bulk tissue. The M-subtype tumors were characterized as “immune-hot” with more immune cell infiltration than the E-subtype ones. The low infiltration of active immune cells, the high infiltration of inactive immune cells, and the high expressions of immune checkpoints demonstrated an immunosuppressive characteristic of the M-subtype tumors. Moreover, we developed and validated a novel prognostic classifier based on the EMT score, the expressions of seven immune checkpoints, and the TNM stages, which could improve the prediction efficiency of the current clinical parameter. Together, our findings provide a better understanding of the tumor immune heterogeneity and may aid guiding immunotherapy in OSCC.
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- 2021
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7. NFAT1 Hypermethylation Promotes Epithelial-Mesenchymal Transition and Metastasis in Nasopharyngeal Carcinoma by Activating ITGA6 Transcription
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Jian Zhang, Zi-Qi Zheng, Ya-Wei Yuan, Pan-Pan Zhang, Ying-Qin Li, Ya-Qin Wang, Xin-Ran Tang, Xin Wen, Xiao-Hong Hong, Yuan Lei, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Jun Ma, and Na Liu
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
DNA methylation is an important epigenetic change in carcinogenesis. However, the function and mechanism of DNA methylation dysregulation in nasopharyngeal carcinoma (NPC) is still largely unclear. Our previous genome-wide microarray data showed that NFAT1 is one of the most hypermethylated transcription factor genes in NPC tissues. Here, we found that NFAT1 hypermethylation contributes to its down-regulation in NPC. NFAT1 overexpression inhibited cell migration, invasion, and epithelial-mesenchymal transition in vitro and tumor metastasis in vivo. We further established that the tumor suppressor effect of NFAT1 is mediated by its inactivation of ITGA6 transcription. Our findings suggest the significance of activating NFAT1/ITGA6 signaling in aggressive NPC, defining a novel critical signaling mechanism that drives NPC invasion and metastasis and providing a novel target for future personalized therapy.
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- 2019
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8. Correction to: Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and tumorigenicity in nasopharyngeal carcinoma by inhibiting cell cycle arrest
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Jian Zhang, Xin Wen, Na Liu, Ying-Qin Li, Xin-Ran Tang, Ya-Qin Wang, Qing-Mei He, Xiao-Jing Yang, Pan-Pan Zhang, Jun Ma, and Ying Sun
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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9. Differential genome-wide profiling of alternative polyadenylation sites in nasopharyngeal carcinoma by high-throughput sequencing
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Ya-Fei Xu, Ying-Qing Li, Na Liu, Qing-Mei He, Xin-Ran Tang, Xin Wen, Xiao-Jing Yang, Ying Sun, Jun Ma, and Ling-Long Tang
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Alternative polyadenylation ,Genome-wide profiling ,High-throughput sequencing ,Nasopharyngeal carcinoma ,Medicine - Abstract
Abstract Background Alternative polyadenylation (APA) is a widespread phenomenon in the posttranscriptional regulation of gene expression that generates mRNAs with alternative 3′-untranslated regions (3’UTRs). APA contributes to the pathogenesis of various diseases, including cancer. However, the potential role of APA in the development of nasopharyngeal carcinoma (NPC) remains largely unknown. Methods A strategy of sequencing APA sites (SAPAS) based on second-generation sequencing technology was carried out to explore the global patterns of APA sites and identify genes with tandem 3’UTRs in samples from 6 NPC and 6 normal nasopharyngeal epithelial tissue (NNET). Sequencing results were then validated using quantitative RT-PCR in a larger cohort of 16 NPC and 16 NNET samples. Results The sequencing data showed that the use of tandem APA sites was prevalent in NPC, and numerous genes with APA-switching events were discovered. In total, we identified 195 genes with significant differences in the tandem 3’UTR length between NPC and NNET; including 119 genes switching to distal poly (A) sites and 76 genes switching to proximal poly (A) sites. Several gene ontology (GO) terms were enriched in the list of genes with switched APA sites, including regulation of cell migration, macromolecule catabolic process, protein catabolic process, proteolysis, small conjugating protein ligase activity, and ubiquitin-protein ligase activity. Conclusions APA site-switching events are prevalent in NPC. APA-mediated regulation of gene expression may play an important role in the development of NPC, and more detailed studies targeting genes with APA-switching events may contribute to the development of novel future therapeutic strategies for NPC.
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- 2018
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10. Integrative evaluation of primary and metastatic lesion spectrum to guide anti-PD-L1 therapy of non-small cell lung cancer: results from two randomized studies
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Si-Cong Ma, Xin-Ran Tang, Li-Li Long, Xue Bai, Jian-Guo Zhou, Zhi-Jiao Duan, Jian Wang, Qiang John Fu, Hong-Bo Zhu, Xue-Jun Guo, Yan-Pei Zhang, Ze-Qin Guo, De-Hua Wu, and Zhong-Yi Dong
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non-small cell lung cancer ,immunotherapy ,tumor burden ,metastasis ,organ ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Objectives: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is heterogeneous in clinical practice. Materials and Methods: We retrospectively assessed the predicitive effect of the primary and metastatic lesion spectrum (baseline sum of the longest diameters [SLD], number of metastatic sites and specific organ metastases) on the efficacy of atezolizumab over docetaxel in OAK and POPLAR trial cohorts. A decision model, termed DSO (Diameter-Site-Organ), based on the spectrum was developed and validated for guiding ICB. Results: Higher SLD (>38 mm) and more metastatic sites (≥2) were characterized with pronounced overall survival (OS) benefits from atezolizumab versus docetaxel. Specifically, adrenal gland and brain metastases were identified as favorable predictors of atezolizumab treatment. The DSO model was developed in the discovery cohort to integrate the directive effect of the primary and metastatic lesion spectrum. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a significantly prolonged OS than docetaxel, whereas OS was generally similar between two treatments in patients with DSO score ≤ 0. Equivalent findings were also seen in the internal and external validation cohorts. Conclusions: The response to anti-PD-L1 therapy among patients varied with the primary and metastatic lesion spectrum. The DSO-based system might provide promising medication guidance for ICB treatment in NSCLC patients.
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- 2021
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11. Development and Validation of a Prognostic Nomogram Based on Residual Tumor in Patients With Nondisseminated Nasopharyngeal Carcinoma
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Ping-Yan Liao MS, Zhong-Yi Dong MD, Chan-Tao Huang BS, Xin-Ran Tang MD, Guan-Dong Liu MS, Zhu-Liu MS, and De-Hua Wu MD
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Objectives: To investigate the prognostic value of residual tumor based on Magnetic resonance imaging(MRI) and establish an effective prognostic nomogram model referring to clinical,pathological and other related factors for predicting prognosis in nasopharyngeal carcinoma. Methods: Overall, 538 patients with non-metastatic, histologically-confirmed nasopharyngeal carcinoma were retrospectively examined. Data from 397 patients were used for the construction and validation of a nomogram based on the presence of residual tumor. A concordance index (C-index) was employed to assess the predictive accuracy and discriminative ability of the nomogram. Results: The 3-year survival rates in the non-residual and residual tumor cohorts were as follows: progression-free survival, 73.4% vs. 61.0%, P = 0.009; locoregional recurrence-free survival, 81.9% vs. 72.0%, P = 0.02; and distant metastasis-free survival, 80.7% vs. 73.5%, P = 0.11. Nine significant factors were included in the nomogram model. The calibration curve for the probability of progression-free survival showed that the nomogram-based predictive values had good concordance with the actual observations. Conclusion: The results showed that the patients in the residual tumor cohorts had a worse prognosis.The proposed nomogram may predict the prognosis and guide clinical decision-making concerning local residual tumors in nasopharyngeal carcinoma patients. Patients with a high risk of progression require more timely and aggressive treatment.
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- 2020
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12. Development and validation of a genomic mutation signature to predict response to PD-1 inhibitors in non-squamous NSCLC: a multicohort stud
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Yi-Long Wu, De-Hua Wu, Si-Cong Ma, Xin-Ran Tang, Shuai Kang, Qiang John Fu, Chuan-Hui Cao, He-San Luo, Yu-Han Chen, Hong-Bo Zhu, Hong-Hong Yan, and Zhong-Yi Dong
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Genetic variations of some driver genes in non-small cell lung cancer (NSCLC) had shown potential impact on immune microenvironment and associated with response or resistance to programmed cell death protein 1 (PD-1) blockade immunotherapy. We therefore undertook an exploratory analysis to develop a genomic mutation signature (GMS) and predict the response to anti-PD-(L)1 therapy.Methods In this multicohort analysis, 316 patients with non-squamous NSCLC treated with anti-PD-(L)1 from three independent cohorts were included in our study. Tumor samples from the patients were molecularly profiled by MSK-IMPACT or whole exome sequencing. We developed a risk model named GMS based on the MSK training cohort (n=123). The predictive model was first validated in the separate internal MSK cohort (n=82) and then validated in an external cohort containing 111 patients from previously published clinical trials.Results A GMS risk model consisting of eight genes (TP53, KRAS, STK11, EGFR, PTPRD, KMT2C, SMAD4, and HGF) was generated to classify patients into high and low GMS groups in the training cohort. Patients with high GMS in the training cohort had longer progression-free survival (hazard ratio (HR) 0.41, 0.28–0.61, p
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- 2020
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13. TIPE3 hypermethylation correlates with worse prognosis and promotes tumor progression in nasopharyngeal carcinoma
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Xian-Yue Ren, Xin Wen, Ying-Qing Li, Jian Zhang, Qing-Mei He, Xiao-Jing Yang, Xin-Ran Tang, Ya-Qin Wang, Pan-Pan Zhang, Xiao-Zhong Chen, Bin Cheng, Jun Ma, and Na Liu
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TIPE3 ,Methylation ,Prognosis ,Proliferation ,Metastasis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Increasing evidence recognizes that DNA methylation abnormalities play critical roles in cancer development. Our previous genome-wide methylation profile showed that tumor necrosis factor-alpha-induced protein 8 like 3 (TIPE3) was hypermethylated in nasopharyngeal carcinoma (NPC). However, the relationship between TIPE3 methylation and its mRNA expression, as well as its biological roles in NPC are unknown. Methods Bisulfite pyrosequencing and quantitative RT-PCR were performed to quantify the TIPE3 methylation and expression levels. Kaplan-Meier curves and Cox regression analysis were used to estimate the correlation between TIPE3 methylation levels and survival in two patient cohorts collected from two hospitals (n = 441). The MTT, colony formation, Transwell migration and invasion assays, and xenograft tumor growth and lung metastatic colonization models were used to identify the functions of TIPE3 on NPC cells. Results We found that TIPE3 CpG island (CGI) was hypermethylated and its mRNA levels were downregulated in many cancers, including NPC. TIPE3 downregulation was associated with its CGI hypermethylation. Furthermore, NPC patients with high TIPE3 CGI methylation levels had poorer clinical outcomes than those with low methylation levels. The TIPE3 CGI methylation level was an independent prognostic factor. Moreover, restoring TIPE3 expression significantly inhibited NPC cell proliferation, migration and invasion in vitro, and suppressed tumor growth and lung metastatic colonization in vivo, while silencing TIPE3 acted in an opposite way. Conclusions TIPE3 downregulation correlates with its CGI hypermethylation in several solid cancers. TIPE3 acts as a tumor suppressor in NPC, providing a further insight into NPC progression and representing a potential prognostic biomarker for NPC.
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- 2018
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14. Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and tumorigenicity in nasopharyngeal carcinoma by inhibiting cell cycle arrest
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Jian Zhang, Xin Wen, Na Liu, Ying-Qin Li, Xin-Ran Tang, Ya-Qin Wang, Qing-Mei He, Xiao-Jing Yang, Pan-Pan Zhang, Jun Ma, and Ying Sun
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ZNF671 ,Hypermethylation ,Proliferation ,Tumorigenicity ,Nasopharyngeal carcinoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Epigenetic abnormalities play important roles in nasopharyngeal cancer (NPC), however, the epigenetic changes associated with abnormal cell proliferation remain unclear. Methods We detected epigenetic change of ZNF671 in NPC tissues and cell lines by bisulfite pyrosequencing. We evaluated zinc finger protein 671 (ZNF671) expression in NPC cell lines and clinical tissues using real-time PCR and western blotting. Then, we established NPC cell lines that stably overexpressed ZNF671 and knocked down ZNF671 expression to explore its function in NPC in vitro and in vivo. Additionally, we investigated the potential mechanism of ZNF671 by identifying the mitotic spindle and G2/M checkpoint pathways pathway downstream genes using gene set enrichment analysis, flow cytometry and western blotting. Results ZNF671 was hypermethylated in NPC tissues and cell lines. The mRNA and protein expression of ZNF671 was down-regulated in NPC tissues and cell lines and the mRNA expression could be upregulated after the demethylation agent 5-aza-2′-deoxycytidine treatment. Overexpression of ZNF671 suppressed NPC cell proliferation and colony formation in vitro; silencing ZNF671 using a siRNA had the opposite effects. Additionally, overexpression of ZNF671 reduced the tumorigenicity of NPC cells in xenograft model in vivo. The mechanism study determined that overexpressing ZNF671 induced S phase arrest in NPC cells by upregulating p21 and downregulating cyclin D1 and c-myc. Conclusions Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and enhances tumorigenicity by inhibiting cell cycle arrest in NPC, which may represent a novel potential therapeutic target.
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- 2017
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15. A Comparison of the Transradial and Transfemoral Approaches for the Angiography and Intervention in Patients with a History of Coronary Artery Bypass Surgery: In-hospital and 1-year Follow-up Results
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Pei-Yuan He, Yue-Jin Yang, Shu-Bin Qiao, Bo Xu, Min Yao, Yong-Jian Wu, Jin-Qing Yuan, Jue Chen, Hai-Bo Liu, Jun Dai, Xin-Ran Tang, Yang Wang, Wei Li, and Run-Lin Gao
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Coronary Angioplasty ,Coronary Artery Bypass Surgery ,Transfemoral ,Transradial ,Medicine - Abstract
Background: Percutaneous coronary intervention (PCI) through transradial approach (TRA) has shown to be safe and effective as transfemoral approach (TFA) among unselected patients. However, very few studies have compared the outcomes between TRA and TFA specifically in patients with a history of coronary artery bypass grafting surgery (CABG). Methods: A total of 404 post-CABG patients who had undergone angiography or PCI were included in the study. The primary endpoint was defined as angiographic success and procedure success. The secondary endpoint was defined as in-hospital net adverse clinical events (NACEs), which included all cause of death, myocardial infarction (MI), stroke, repeat revascularization, and major bleeding. Patients were followed-up for 1-year. Major adverse cardiovascular events (MACEs), which included death, MI, and repeat revascularization, at 1-year follow-up were also compared. Results: The angiographic success was reached by 97.4% in the TRA group compared with 100% in the TFA group (P = 0.02). The procedure success was achieved in 99.1% in the TRA group and 97.9% in the TFA group (P = 0.68). The incidence rates of in-hospital NACE (2.7% vs. 2.7%, P = 1.00) and 1-year MACE (11.5% vs. 12.0%, P = 0.88) were similar between TRA and TFA. Meanwhile, TRA was associated with a lower rate of Bleeding Academic Research Consortium ≥2 bleeding (P = 0.02). In patients undergoing graft PCI, the procedure success was similar between TRA and TFA (100.0% vs. 98.7%, P = 1.00). The procedure time (25.0 min vs. 27.5 min, P = 0.53) was also similar. No significant difference was detected between TRA and TFA in terms of in-hospital NACE (0 vs. 0, P = 1.00) and 1-year MACE (21.4% vs. 10.3%, P = 0.19). Conclusions: Compared with TFA, TRA had lower angiographic success but had a similar procedure success in post-CABG patients. TRA was also associated with decreased bleeding and shortened hospital stay.
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- 2015
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16. Costs and Benefits Associated With Transradial Versus Transfemoral Percutaneous Coronary Intervention in China
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Chen Jin, Wei Li, Shu‐Bin Qiao, Jin‐Gang Yang, Yang Wang, Pei‐Yuan He, Xin‐Ran Tang, Qiu‐Ting Dong, Xiang‐Dong Li, Hong‐Bing Yan, Yong‐Jian Wu, Ji‐Lin Chen, Run‐Lin Gao, Jin‐Qing Yuan, Ke‐Fei Dou, Bo Xu, Wei Zhao, Xue Zhang, Ying Xian, and Yue‐Jin Yang
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coronary artery disease ,cost ,health services research ,interventional cardiology ,outcomes research ,percutaneous coronary intervention ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundTransradial percutaneous coronary intervention (PCI) has been increasingly adopted in clinical practice, given its potential advantages over transfemoral intervention; however, the impact of different access strategies on costs and clinical outcomes remains poorly defined, especially in the developing world. Methods and ResultsUsing data from a consecutive cohort of 5306 patients undergoing PCI in China in 2010, we compared total hospital costs and in‐hospital outcomes for transradial intervention (TRI) and transfemoral intervention. Patients receiving TRI (n=4696, 88.5%) were slightly younger (mean age 57.4 versus 59.5 years), less often women (21.6% versus 33.1%), more likely to undergo PCI for single‐vessel disease, and less likely to undergo PCI for triple‐vessel or left main diseases. The unadjusted total hospital costs were 57 900 Chinese yuan (¥57 900; equivalent to 9190 US dollars [$9190]) for TRI and ¥67 418 ($10,701) for transfemoral intervention. After adjusting for all observed patient and procedural characteristics using the propensity score inverse probability weighting method, TRI was associated with a lower total cost (adjusted difference ¥8081 [$1283]). More than 80% of the cost difference was related to lower PCI‐related costs (adjusted difference −¥5162 [−$819]), which were likely driven by exclusive use of vascular closure devices in transfemoral intervention, and lower hospitalization costs (−¥1399 [−$222]). Patients receiving TRI had shorter length of stay and were less likely to experience major adverse cardiac events or post‐PCI bleeding. These differences were consistent among clinically relevant subgroups with acute myocardial infarction, acute coronary syndrome, and stable angina. ConclusionsAmong patients undergoing PCI, TRI was associated with lower cost and favorable clinical outcomes compared with transfemoral intervention.
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- 2016
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17. supplemental figure 1 from Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC
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Jun Ma, Na Liu, Xiao-Jing Yang, Qing-Mei He, Xin Wen, Xin-Ran Tang, Ying-Qin Li, Ya-Fei Xu, Ying Sun, Wei Jiang, Guan-Qun Zhou, and Xian-Yue Ren
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Supplemental Figure 1. The SFRP1 mRNA (A) and protein (B) expression of CNE-2 and SUNE-1 cells transfected with plasmid pcDNA3.1-SFRP1 compared to the original cell lines and the pcDNA3.1-vector.
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- 2023
18. supplemental figure 2 from Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC
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Jun Ma, Na Liu, Xiao-Jing Yang, Qing-Mei He, Xin Wen, Xin-Ran Tang, Ying-Qin Li, Ya-Fei Xu, Ying Sun, Wei Jiang, Guan-Qun Zhou, and Xian-Yue Ren
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Supplemental Figure 2. (A)The SFRP1 mRNA and protein expression of NP69 cells transfected with SFRP1 siRNA compared with the original cell lines and the control siRNA-NC; Effects of SFRP1 siRNA on NP69 cell proliferation(B), migration (C and D).
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- 2023
19. Supplemental Methods and Materials from Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC
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Jun Ma, Na Liu, Xiao-Jing Yang, Qing-Mei He, Xin Wen, Xin-Ran Tang, Ying-Qin Li, Ya-Fei Xu, Ying Sun, Wei Jiang, Guan-Qun Zhou, and Xian-Yue Ren
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Supplemental Methods and Materials
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- 2023
20. Data from Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC
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Jun Ma, Na Liu, Xiao-Jing Yang, Qing-Mei He, Xin Wen, Xin-Ran Tang, Ying-Qin Li, Ya-Fei Xu, Ying Sun, Wei Jiang, Guan-Qun Zhou, and Xian-Yue Ren
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Distant metastasis remains the predominant mode of treatment failure in nasopharyngeal carcinoma (NPC). Unfortunately, the molecular events underlying NPC metastasis remain poorly understood. Secreted frizzled-related protein 1 (SFRP1) plays an important role in tumorigenesis and progression. However, little is known about the function and mechanism of SFRP1 in NPC. Immunohistochemistry was used to determine SFRP1 expression levels in patients with NPC. SFRP1 function was evaluated using MTT, colony formation, wound-healing, Transwell assays, and in vivo models. The methylation level of SFRP1 in NPC cells was examined using bisulfate pyrosequencing; the Wnt/β-catenin signaling pathway genes were studied using Western blotting. Compared with patients with high SFRP1 expression, patients with low SFRP1 expression had worse overall survival [HR, 2.32; 95% confidence interval (CI), 1.36–3.94; P = 0.002], disease-free survival (HR, 1.98; 95% CI, 1.23–3.18; P = 0.005), and distant metastasis-free survival (HR, 2.07; 95% CI, 1.19–3.59; P = 0.009). Multivariate Cox regression analysis indicated that SFRP1 was an independent prognostic factor. Furthermore, SFRP1 was significantly downregulated in NPC cell lines. SFRP1 overexpression suppressed NPC cell proliferation, migration, and invasion in vitro and lung colonization in vivo. SFRP1 expression was restored after treatment with a demethylation agent, and the SFRP1 promoter region was hypermethylated in NPC cells. β-Catenin, c-Myc, and cyclin D1 were downregulated after SFRP1 restoration, which suggested that SFRP1 suppressed growth and metastasis by inhibiting the Wnt/β-catenin signaling pathway in NPC. SFRP1 provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment. Cancer Prev Res; 8(10); 968–77. ©2015 AACR.
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- 2023
21. Figure S2 from Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
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Zhong-Yi Dong, Zhu Liu, Xue-Jun Guo, Qin Zeng, Ze-Qin Guo, Yuan Fang, Hong-Bo Zhu, Yao-Wei Zhang, Xiu-Ju Du, Sha-Sha Du, De-Hua Wu, Xin-Ran Tang, Jian Wang, Xue Bai, and Li Liu
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Relationship between CNA level and TMB in (A) MSK pan-cancer non-ICI treated cohort and (B) other three ICI-treated cohorts (MSK NSCLC, SKCM, and Dana-Farber ICI cohort). For each cancer type and each cohort, a plot is shown containing the CNA level versus tumor mutation burden. The spearman correlation coefficient and P value are shown.
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- 2023
22. Table S1 from Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
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Zhong-Yi Dong, Zhu Liu, Xue-Jun Guo, Qin Zeng, Ze-Qin Guo, Yuan Fang, Hong-Bo Zhu, Yao-Wei Zhang, Xiu-Ju Du, Sha-Sha Du, De-Hua Wu, Xin-Ran Tang, Jian Wang, Xue Bai, and Li Liu
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Demographic and clinicopathologic characteristics of three cohorts treated with immune checkpoint inhibitors.
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- 2023
23. Data from Hypermethylation of SHISA3 Promotes Nasopharyngeal Carcinoma Metastasis by Reducing SGSM1 Stability
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Na Liu, Jun Ma, Ying Sun, Xiao-Jing Yang, Qing-Mei He, Yuan Lei, Xiao-Hong Hong, Xin Wen, Xin-Ran Tang, Pan-Pan Zhang, Ya-Qin Wang, Rui Guo, Ying-Qin Li, and Jian Zhang
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Altered DNA methylation is a key feature of cancer, and aberrant methylation is important in nasopharyngeal carcinoma (NPC) development. However, the methylation mechanisms underlying metastasis of NPC remain unclear. Analyzing data from public databases and conducting our own experiments, we report here that promoter hypermethylation of SHISA3 is common and contributes to the downregulation of this gene in many types of tumors, including NPC. SHISA3 suppressed NPC cell invasion and metastasis in vitro and in vivo by impeding the E3 ubiquitin ligase tripartite motif containing 21 (TRIM21)–mediated ubiquitination and degradation small G protein signaling modulator 1 (SGSM1) and by inhibiting the MAPK pathway activation. Silencing SGSM1 abrogated the inhibitory effect of SHISA3 on NPC cell migration and invasion. This newly identified SHISA3–TRIM21–SGSM1 axis could be a novel therapeutic target in NPC.Significance:These findings highlight the mechanism by which a newly identified tumor suppressor SHISA3 suppresses invasion and metastasis of nasopharyngeal carcinoma.
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- 2023
24. Supplementary Data from Hypermethylation of SHISA3 Promotes Nasopharyngeal Carcinoma Metastasis by Reducing SGSM1 Stability
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Na Liu, Jun Ma, Ying Sun, Xiao-Jing Yang, Qing-Mei He, Yuan Lei, Xiao-Hong Hong, Xin Wen, Xin-Ran Tang, Pan-Pan Zhang, Ya-Qin Wang, Rui Guo, Ying-Qin Li, and Jian Zhang
- Abstract
Supplementary Figures S1-S8: -Figure S1. The SHISA3 promoter is hypermethylated in NPC. Figure S2. The SHISA3 promoter is hypermethylated in NPC cell lines. Figure S3. SHISA3 is hypermethylated in 18 primary solid tumors. Figure S4. Correlations between SHISA3 promoter methylation and mRNA expression in primary solid tumors. Figure S5. SHISA3 has little effect on NPC cell proliferation in vitro. Figure S6. SHISA3 stabilizes SGSM1 by impeding TRIM21-mediated deubiquitination. Figure S7. The effects of SHISA3 overexpression on nasopharyngeal carcinoma aggressiveness in vivo. Figure S8. SHISA3 has little effect on the canonical Wnt signaling pathway.
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- 2023
25. Supplementary figure legends from Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
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Zhong-Yi Dong, Zhu Liu, Xue-Jun Guo, Qin Zeng, Ze-Qin Guo, Yuan Fang, Hong-Bo Zhu, Yao-Wei Zhang, Xiu-Ju Du, Sha-Sha Du, De-Hua Wu, Xin-Ran Tang, Jian Wang, Xue Bai, and Li Liu
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Supplementary figure legends
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- 2023
26. Data from Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
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Zhong-Yi Dong, Zhu Liu, Xue-Jun Guo, Qin Zeng, Ze-Qin Guo, Yuan Fang, Hong-Bo Zhu, Yao-Wei Zhang, Xiu-Ju Du, Sha-Sha Du, De-Hua Wu, Xin-Ran Tang, Jian Wang, Xue Bai, and Li Liu
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Purpose:Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu.Experimental Design:Non-ICI–treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non–small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy.Results:TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI–treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors.Conclusions:The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.
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- 2023
27. Corrigendum to 'NFAT1 hypermethylation promotes epithelial‐mesenchymal transition and metastasis in nasopharyngeal carcinoma by activating ITGA6 transcription' [Neoplasia 21 (2019): 311–321]
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Yuan Lei, Xiao-Hong Hong, Na Liu, Ying-Qin Li, Pan-Pan Zhang, Jian Zhang, Yawei Yuan, Xiao-Jing Yang, Ya-Qin Wang, Xin Wen, Jun Ma, Ying Sun, Qingmei He, Zi-Qi Zheng, and Xin-Ran Tang
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Transcriptional Activation ,Cancer Research ,Epithelial-Mesenchymal Transition ,Integrin alpha6 ,Epigenesis, Genetic ,Metastasis ,Transcription (biology) ,Cell Line, Tumor ,medicine ,Humans ,Epithelial–mesenchymal transition ,RC254-282 ,Neoplasm Staging ,Nasopharyngeal Carcinoma ,NFATC Transcription Factors ,business.industry ,Gene Expression Profiling ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,DNA Methylation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Nasopharyngeal carcinoma ,Lymphatic Metastasis ,DNA methylation ,Cancer research ,RNA Interference ,Corrigendum ,Transcriptome ,business ,ITGA6 - Abstract
DNA methylation is an important epigenetic change in carcinogenesis. However, the function and mechanism of DNA methylation dysregulation in nasopharyngeal carcinoma (NPC) is still largely unclear. Our previous genome-wide microarray data showed that NFAT1 is one of the most hypermethylated transcription factor genes in NPC tissues. Here, we found that NFAT1 hypermethylation contributes to its down-regulation in NPC. NFAT1 overexpression inhibited cell migration, invasion, and epithelial-mesenchymal transition in vitro and tumor metastasis in vivo. We further established that the tumor suppressor effect of NFAT1 is mediated by its inactivation of ITGA6 transcription. Our findings suggest the significance of activating NFAT1/ITGA6 signaling in aggressive NPC, defining a novel critical signaling mechanism that drives NPC invasion and metastasis and providing a novel target for future personalized therapy.
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- 2021
28. Comprehensive Characterization of Immune Landscape Based on Epithelial-Mesenchymal Transition Signature in OSCC: Implication for Prognosis and Immunotherapy
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Xianyue Ren, Xijuan Chen, Wei-lin Zhang, Tong Wu, Ruoyan Cao, Qin Liu, Jia-Ying Zhou, Xue Pan, Si-yuan Zhang, Bin Cheng, Chunyang Wang, and Xin-Ran Tang
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0301 basic medicine ,Cancer Research ,animal diseases ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Stroma ,medicine ,tumor microenvironment ,Epithelial–mesenchymal transition ,immune checkpoint ,RC254-282 ,Original Research ,Tumor microenvironment ,Mesenchymal stem cell ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,epithelial to mesenchymal transition ,Immunotherapy ,biochemical phenomena, metabolism, and nutrition ,Immune checkpoint ,oral squamous cell carcinoma ,stomatognathic diseases ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,bacteria ,prognosis - Abstract
Current anatomic TNM stage classification fails to capture the immune heterogeneity of oral squamous cell carcinoma (OSCC). Increasing evidence indicates the strong association between epithelial-mesenchymal transition (EMT) and tumor immune response. In this study, we employed an EMT signature to classify OSCC patients into epithelial- (E-) and mesenchymal- (M-) phenotypes using TCGA and GSE41613 transcriptome data. The ESTIMATE and CIRBERSORT analyses implied that the EMT signature genes originated from the stroma of the bulk tissue. The M-subtype tumors were characterized as “immune-hot” with more immune cell infiltration than the E-subtype ones. The low infiltration of active immune cells, the high infiltration of inactive immune cells, and the high expressions of immune checkpoints demonstrated an immunosuppressive characteristic of the M-subtype tumors. Moreover, we developed and validated a novel prognostic classifier based on the EMT score, the expressions of seven immune checkpoints, and the TNM stages, which could improve the prediction efficiency of the current clinical parameter. Together, our findings provide a better understanding of the tumor immune heterogeneity and may aid guiding immunotherapy in OSCC.
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- 2021
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29. Hypermethylation of SHISA3 Promotes Nasopharyngeal Carcinoma Metastasis by Reducing SGSM1 Stability
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Xiao-Jing Yang, Ying Sun, Yuan Lei, Rui Guo, Na Liu, Xin-Ran Tang, Pan Pan Zhang, Ya Qin Wang, Xin Wen, Ying Qin Li, Xiao Hong Hong, Jian Zhang, Jun Ma, and Qing Mei He
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0301 basic medicine ,Regulation of gene expression ,Cancer Research ,biology ,Cell migration ,Methylation ,medicine.disease ,Ubiquitin ligase ,Metastasis ,stomatognathic diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,DNA methylation ,otorhinolaryngologic diseases ,biology.protein ,Cancer research ,medicine ,Small G protein signaling modulator 1 - Abstract
Altered DNA methylation is a key feature of cancer, and aberrant methylation is important in nasopharyngeal carcinoma (NPC) development. However, the methylation mechanisms underlying metastasis of NPC remain unclear. Analyzing data from public databases and conducting our own experiments, we report here that promoter hypermethylation of SHISA3 is common and contributes to the downregulation of this gene in many types of tumors, including NPC. SHISA3 suppressed NPC cell invasion and metastasis in vitro and in vivo by impeding the E3 ubiquitin ligase tripartite motif containing 21 (TRIM21)–mediated ubiquitination and degradation small G protein signaling modulator 1 (SGSM1) and by inhibiting the MAPK pathway activation. Silencing SGSM1 abrogated the inhibitory effect of SHISA3 on NPC cell migration and invasion. This newly identified SHISA3–TRIM21–SGSM1 axis could be a novel therapeutic target in NPC. Significance: These findings highlight the mechanism by which a newly identified tumor suppressor SHISA3 suppresses invasion and metastasis of nasopharyngeal carcinoma.
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- 2019
30. Integrative evaluation of primary and metastatic lesion spectrum to guide anti-PD-L1 therapy of non-small cell lung cancer: results from two randomized studies
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Xue Bai, Zhong-Yi Dong, Xin-Ran Tang, Si-Cong Ma, Hong-Bo Zhu, Dehua Wu, Jian-Guo Zhou, Zhi-Jiao Duan, Jian Wang, Li-Li Long, Xue-Jun Guo, Yan-Pei Zhang, Ze-Qin Guo, and Qiang John Fu
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Immunology ,Docetaxel ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Non-small cell lung cancer ,Atezolizumab ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,organ ,medicine ,metastasis ,Humans ,Immunology and Allergy ,Lung cancer ,RC254-282 ,Original Research ,Retrospective Studies ,Chemotherapy ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Antibodies, Monoclonal ,Immunotherapy ,RC581-607 ,medicine.disease ,Blockade ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,immunotherapy ,Immunologic diseases. Allergy ,business ,tumor burden ,Research Article ,medicine.drug - Abstract
Objectives: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is heterogeneous in clinical practice. Materials and Methods: We retrospectively assessed the predicitive effect of the primary and metastatic lesion spectrum (baseline sum of the longest diameters [SLD], number of metastatic sites and specific organ metastases) on the efficacy of atezolizumab over docetaxel in OAK and POPLAR trial cohorts. A decision model, termed DSO (Diameter-Site-Organ), based on the spectrum was developed and validated for guiding ICB. Results: Higher SLD (>38 mm) and more metastatic sites (≥2) were characterized with pronounced overall survival (OS) benefits from atezolizumab versus docetaxel. Specifically, adrenal gland and brain metastases were identified as favorable predictors of atezolizumab treatment. The DSO model was developed in the discovery cohort to integrate the directive effect of the primary and metastatic lesion spectrum. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a significantly prolonged OS than docetaxel, whereas OS was generally similar between two treatments in patients with DSO score ≤ 0. Equivalent findings were also seen in the internal and external validation cohorts. Conclusions: The response to anti-PD-L1 therapy among patients varied with the primary and metastatic lesion spectrum. The DSO-based system might provide promising medication guidance for ICB treatment in NSCLC patients.
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- 2021
31. Development and validation of a genomic mutation signature to predict response to PD-1 inhibitors in non-squamous NSCLC: a multicohort stud
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Xue Bai, Qiang John Fu, Hesan Luo, Yi-Long Wu, Zhong-Yi Dong, Jian Wang, Hong-Bo Zhu, Yuhan Chen, Dehua Wu, Chuanhui Cao, Hong-Hong Yan, Shuai Kang, Si-Cong Ma, and Xin-Ran Tang
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,STK11 ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Immunology and Allergy ,Exome sequencing ,RC254-282 ,Pharmacology ,business.industry ,Hazard ratio ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,Clinical trial ,030104 developmental biology ,Genetic marker ,030220 oncology & carcinogenesis ,Cohort ,Molecular Medicine ,KRAS ,business - Abstract
BackgroundGenetic variations of some driver genes in non-small cell lung cancer (NSCLC) had shown potential impact on immune microenvironment and associated with response or resistance to programmed cell death protein 1 (PD-1) blockade immunotherapy. We therefore undertook an exploratory analysis to develop a genomic mutation signature (GMS) and predict the response to anti-PD-(L)1 therapy.MethodsIn this multicohort analysis, 316 patients with non-squamous NSCLC treated with anti-PD-(L)1 from three independent cohorts were included in our study. Tumor samples from the patients were molecularly profiled by MSK-IMPACT or whole exome sequencing. We developed a risk model named GMS based on the MSK training cohort (n=123). The predictive model was first validated in the separate internal MSK cohort (n=82) and then validated in an external cohort containing 111 patients from previously published clinical trials.ResultsA GMS risk model consisting of eight genes (TP53, KRAS, STK11, EGFR, PTPRD, KMT2C, SMAD4, and HGF) was generated to classify patients into high and low GMS groups in the training cohort. Patients with high GMS in the training cohort had longer progression-free survival (hazard ratio (HR) 0.41, 0.28–0.61, p<0.0001) and overall survival (HR 0.53, 0.32–0.89, p=0.0275) compared with low GMS. We noted equivalent findings in the internal validation cohort and in the external validation cohort. The GMS was demonstrated as an independent predictive factor for anti-PD-(L)1 therapy comparing with tumor mutational burden. Meanwhile, GMS showed undifferentiated predictive value in patients with different clinicopathological features. Notably, both GMS and PD-L1 were independent predictors and demonstrated poorly correlated; inclusion of PD-L1 with GMS further improved the predictive capacity for PD-1 blockade immunotherapy.ConclusionsOur study highlights the potential predictive value of GMS for immunotherapeutic benefit in non-squamous NSCLC. Besides, the combination of GMS and PD-L1 may serve as an optimal partner in guiding treatment decisions for anti-PD-(L)1 based therapy.
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- 2020
32. Integrative Modeling of Tumor Burden and Metastatic Pattern for Guiding Anti-PD-L1 Treatment of Non–Small Cell Lung Cancer: Results From Two Randomized Studies
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Li-Li Long, Zhi-Jiao Duan, Xue Bai, Jian Wang, Dehua Wu, Si-Cong Ma, Hong-Bo Zhu, Ze-Qin Guo, Xue-Jun Guo, Xin-Ran Tang, Yan-Pei Zhang, Qiang John Fu, and Zhong-Yi Dong
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Oncology ,Chemotherapy ,medicine.medical_specialty ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Population ,medicine.disease ,Docetaxel ,Informed consent ,Atezolizumab ,Internal medicine ,Cohort ,medicine ,Lung cancer ,education ,business ,medicine.drug - Abstract
Background: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is still heterogeneous in clinical practice. Methods: We retrospectively assessed the impact of baseline sum of the longest diameters (SLD), number of metastatic sites and specific organ metastases on the efficacy of atezolizumab versus docetaxel in the pooled population from OAK and POPLAR studies. An assistant decision model based on the machine-learning method, incorporating these indicators, termed DSO (Diameter-Site-Organ), was developed and validated in OAK and POPLAR cohorts. Findings: Higher SLD (> 38mm) and more metastatic sites (≥ 2) were characterized with pronounced OS benefits from atezolizumab versus docetaxel. Specifically, brain and adrenal gland metastases were identified as favorable predictors of atezolizumab treatment. The DSO model for guiding second-line treatment was developed based on SLD and metastatic sites and organs in the discovery cohort. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a prolonged OS than docetaxel (hazard ratio [HR] 0.67, 95% CI 0.54-0.84; P = 0.0003), whereas OS was generally similar between two treatments in patients with DSO score ≤ 0 (HR 1.46, 95% CI 0.89-2.39; P = 0.1346). Equivalent findings were seen in the internal and external validation cohorts. Interpretation: Our study for the first time revealed that patients with higher tumor burden were more suitable for ICB compared with standard chemotherapy. More importantly, the integrative DSO decision model might provide promising medication guidance for second-line ICB treatment in unselected NSCLC patients. Funding: This study was supported by the National Natural Science Foundation for YoungScientists of China (Grant No. 81802863 and 81902353), the Natural Science Foundation of Guangdong Province (Grant No. 2018030310285), and the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University (Grant No. 2017J003). Conflict of Interest: The authors have no actual or potential conflicts of interest to declare. Ethical Approval: The study was approved by theInstitutional Ethical Review Boards of Nanfang Hospital. All patients enrolled in OAK and POPLAR provided signed informed consent in accordance with the protocols of the corresponding studies.
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- 2020
33. RAB37 Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma
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Xin-Ran Tang, Qingmei He, Xiao-Jing Yang, Xiao-Hong Hong, Xiao-Jing Du, Ying Qin Li, Yuan Lei, Jun Ma, Xin Wen, Ying Sun, Jian Zhang, Na Liu, Ya-Qin Wang, and Pan-Pan Zhang
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0301 basic medicine ,Regulation of gene expression ,Cancer Research ,MMP2 ,business.industry ,medicine.disease ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,Oncology ,Downregulation and upregulation ,Nasopharyngeal carcinoma ,Docetaxel ,DNA methylation ,Cancer research ,medicine ,Epigenetics ,business ,medicine.drug - Abstract
Purpose: Epigenetic alterations play important roles in metastasis and drug resistance through gene regulation. However, the functional features and molecular mechanisms of epigenetic changes remain largely unclear in nasopharyngeal carcinoma (NPC) metastasis. Experimental Design: Gene regulatory network analysis was used to identify metastatic-specific dysregulated genes between normal and NPC tissues and the expression was validated in published Gene-Expression Omnibus data set. The regulatory and functional role of RAB37 downregulation was examined in NPC and was validated in vitro and in vivo, and downstream target of RAB37 was explored. The clinical value of RAB37 methylation was evaluated in NPC metastasis and chemosensitivity. Results: We identified RAB37 as a specific hypermethylated gene that is most commonly downregulated in NPC. Moreover, RAB37 downregulation was attributed to hypermethylation of its promoter and was significantly associated with metastasis- and docetaxel chemoresistance-related features in NPC. Ectopic RAB37 overexpression suppressed NPC cell metastasis and enhanced chemosensitivity to docetaxel. Mechanistically, RAB37 colocalized with TIMP2, regulated TIMP2 secretion, inhibited downstream MMP2 activity, and consequently altered NPC cell metastasis. Furthermore, RAB37 hypermethylation was correlated with poor clinical outcomes in patients with NPC. We developed a prognostic model based on RAB37 methylation and N stage that effectively predicted an increased risk of distant metastasis and a favorable response to docetaxel-containing induction chemotherapy (IC) in NPC patients. Conclusions: This study shows that RAB37 hypermethylation is involved in NPC metastasis and chemoresistance, and that our prognostic model can identify patients who are at a high risk of distant metastasis and might benefit from for docetaxel IC.
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- 2018
34. Development and validation of a gene expression-based signature to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma: a retrospective, multicentre, cohort study
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Ya Qin Wang, Shao Bo Liang, Jing Ping Yun, Na Liu, Jun Ma, Pan Pan Zhang, Ying Qin Li, Xiao-Jing Yang, Li Li, Ling Long Tang, Wen Xiu Ge, Xin Wen, Yan Ping Mao, Wei Jiang, Li Zhi Liu, Jian Zhang, Fang Liu, Xin-Ran Tang, Qing Mei He, Jing Zeng, Ying Sun, and Yuan Zhang
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Adult ,Male ,0301 basic medicine ,Oncology ,China ,medicine.medical_specialty ,Clinical Decision-Making ,Risk Assessment ,Decision Support Techniques ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,Neoplasm Invasiveness ,Progression-free survival ,Neoplasm Staging ,Oligonucleotide Array Sequence Analysis ,Retrospective Studies ,Nasopharyngeal Carcinoma ,business.industry ,Gene Expression Profiling ,Hazard ratio ,Reproducibility of Results ,Nasopharyngeal Neoplasms ,Retrospective cohort study ,Middle Aged ,Nomogram ,Gene signature ,medicine.disease ,Progression-Free Survival ,Nomograms ,030104 developmental biology ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,Cohort ,Female ,Transcriptome ,business ,Cohort study - Abstract
Gene expression patterns can be used as prognostic biomarkers in various types of cancers. We aimed to identify a gene expression pattern for individual distant metastatic risk assessment in patients with locoregionally advanced nasopharyngeal carcinoma.In this multicentre, retrospective, cohort analysis, we included 937 patients with locoregionally advanced nasopharyngeal carcinoma from three Chinese hospitals: the Sun Yat-sen University Cancer Center (Guangzhou, China), the Affiliated Hospital of Guilin Medical University (Guilin, China), and the First People's Hospital of Foshan (Foshan, China). Using microarray analysis, we profiled mRNA gene expression between 24 paired locoregionally advanced nasopharyngeal carcinoma tumours from patients at Sun Yat-sen University Cancer Center with or without distant metastasis after radical treatment. Differentially expressed genes were examined using digital expression profiling in a training cohort (Guangzhou training cohort; n=410) to build a gene classifier using a penalised regression model. We validated the prognostic accuracy of this gene classifier in an internal validation cohort (Guangzhou internal validation cohort, n=204) and two external independent cohorts (Guilin cohort, n=165; Foshan cohort, n=158). The primary endpoint was distant metastasis-free survival. Secondary endpoints were disease-free survival and overall survival.We identified 137 differentially expressed genes between metastatic and non-metastatic locoregionally advanced nasopharyngeal carcinoma tissues. A distant metastasis gene signature for locoregionally advanced nasopharyngeal carcinoma (DMGN) that consisted of 13 genes was generated to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter distant metastasis-free survival (hazard ratio [HR] 4·93, 95% CI 2·99-8·16; p0·0001), disease-free survival (HR 3·51, 2·43-5·07; p0·0001), and overall survival (HR 3·22, 2·18-4·76; p0·0001) than patients with low-risk scores. The prognostic accuracy of DMGN was validated in the internal and external cohorts. Furthermore, among patients with low-risk scores in the combined training and internal cohorts, concurrent chemotherapy improved distant metastasis-free survival compared with those patients who did not receive concurrent chemotherapy (HR 0·40, 95% CI 0·19-0·83; p=0·011), whereas patients with high-risk scores did not benefit from concurrent chemotherapy (HR 1·03, 0·71-1·50; p=0·876). This was also validated in the two external cohorts combined. We developed a nomogram based on the DMGN and other variables that predicted an individual's risk of distant metastasis, which was strengthened by adding Epstein-Barr virus DNA status.The DMGN is a reliable prognostic tool for distant metastasis in patients with locoregionally advanced nasopharyngeal carcinoma and might be able to predict which patients benefit from concurrent chemotherapy. It has the potential to guide treatment decisions for patients at different risk of distant metastasis.The National Natural Science Foundation of China, the National ScienceTechnology Pillar Program during the Twelfth Five-year Plan Period, the Natural Science Foundation of Guang Dong Province, the National Key Research and Development Program of China, the Innovation Team Development Plan of the Ministry of Education, the HealthMedical Collaborative Innovation Project of Guangzhou City, China, and the Program of Introducing Talents of Discipline to Universities.
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- 2018
35. Prognostic significance of tumor-infiltrating lymphocytes in nondisseminated nasopharyngeal carcinoma: A large-scale cohort study
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Xiao-Jing Yang, Pan Pan Zhang, Ying Qin Li, Wei Jiang, Yu Pei Chen, Ya Qin Wang, Jing Ping Yun, Yuan Lei, Jun Ma, Qing Mei He, Xin Wen, Jian Zhang, Na Liu, Yu Zhang, Xin-Ran Tang, and Ying Sun
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Proportional hazards model ,business.industry ,Hazard ratio ,Cancer ,Nomogram ,medicine.disease ,Confidence interval ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,medicine ,business ,Cohort study - Abstract
The American Joint Committee on Cancer (AJCC) staging system is inadequate for an accurate prognosis in nasopharyngeal carcinoma (NPC). Thus, new biomarkers are under intense investigation. Here, we investigated whether the density of TILs could predict prognosis in NPC. First, we used 1490 cases of nasopharyngeal carcinoma samples from two independent cohorts to evaluate the density and distribution of tumor-infiltrating lymphocytes (TILs). Second, in one cohort, we assessed associations between TILs and clinical outcomes in 593 randomly selected samples (defined as the training set) and validated findings in the remaining 593 samples (defined as the validation set). Furthermore, we confirmed the prognostic value of TILs in a second independent cohort of 304 cases (defined as the independent set). Based on multivariable Cox regression analysis, we also established an effective prognostic nomogram including TILs to improve accuracy in predicting disease-free survival (DFS) for patients with nondisseminated NPC. We found that high TILs in the training set were significantly associated with favorable DFS [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.28-0.58, p < 0.001], overall survival (OS, HR 0.42, 95% CI 0.27-0.64, p < 0.001), distant metastasis-free survival (DMFS, HR 0.37, 95% CI 0.23-0.58, p < 0.001) and local-regional recurrent free survival (LRRFS, HR 0.43, 95% CI 0.25-0.73, p = 0.002). Multivariate analysis showed that TILs are an independent prognostic indicator for DFS in all cohorts. In summary, this study indicated that TILs may reflect the immunological heterogeneity of NPC and could represent a new prognostic biomarker.
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- 2018
36. The feasibility of contralateral lower neck sparing intensity modulation radiated therapy for nasopharyngeal carcinoma patients with unilateral cervical lymph node involvement
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Li Tian, Ying Sun, Ai Hua Lin, Lei Chen, Xin-Ran Tang, Jun Ma, Ling Long Tang, and Wen Fei Li
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Lymph node metastasis ,030218 nuclear medicine & medical imaging ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,medicine ,Humans ,Lymph node ,Aged ,NECK IRRADIATION ,medicine.diagnostic_test ,business.industry ,Head and neck cancer ,Nasopharyngeal Neoplasms ,Magnetic resonance imaging ,Chemoradiotherapy ,Middle Aged ,medicine.disease ,Surgery ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,Nasopharyngeal carcinoma ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Feasibility Studies ,Female ,Radiotherapy, Intensity-Modulated ,Radiology ,Oral Surgery ,business ,Intensity modulation ,Neck ,Entire neck - Abstract
Objectives To investigate the feasibility of contralateral lower neck sparing intensity modulation radiated therapy (IMRT) for nasopharyngeal carcinoma patients (NPC) with unilateral cervical lymph node metastasis. Materials and methods Retrospective review of 546 patients with unilateral cervical lymph node metastasis treated between November 2009 and February 2012 at one institution. All patients were staged using magnetic resonance imaging and received radical IMRT. Patients were classified into two groups: the inferior border of the negative neck irradiation field only covered Levels III to Va in Group 1; the inferior border covered entire neck down to Levels IV to Vb in Group 2. Results Median follow-up was 49.9 months (range, 1.3–69.2 months). Four-year overall survival (OS:89.3% vs. 88.9%, P = 0.91), disease-free survival (DFS:81.7% vs. 81.0%, P = 0.91), distant metastasis-free survival (DMFS:88.2% vs. 87.9%, P = 0.95), local relapse-free survival (LRFS:96.7% vs. 94.7%, P = 0.70) and nodal relapse-free survival (NRFS: 96.1% vs. 95.9%, P = 0.94) were not significantly different between Group 1 and Group 2. Twenty-two patients developed cervical lymph node relapse; of whom 20/22 (91.0%) developed unilateral relapse within pretreatment positive neck. Only one patient developed out-of-field relapse, though this patient also relapsed within the neck irradiation field (Level II). No clinicopathological feature tested had significant prognostic value for NRFS in multivariate analysis. Conclusions In the IMRT and MRI era, contralateral lower neck sparing IMRT seems to be feasible for NPC patients with unilateral cervical lymph node metastasis.
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- 2017
37. HOPX hypermethylation promotes metastasis via activating SNAIL transcription in nasopharyngeal carcinoma
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Na Liu, Qian Zhong, Tianpeng Zhang, Ying-Qin Li, Xiaozhong Chen, Jun Ma, Xin-Ran Tang, Qingmei He, Xianyue Ren, Bin Cheng, Xin Wen, Bin Li, Tiebang Kang, Mu Sheng Zeng, and Xiao-Jing Yang
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Transcriptional Activation ,0301 basic medicine ,Science ,Transplantation, Heterologous ,Mice, Nude ,General Physics and Astronomy ,Kaplan-Meier Estimate ,Snail ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,Histones ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,biology.animal ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Epigenetics ,Neoplasm Metastasis ,Promoter Regions, Genetic ,Transcription factor ,Homeodomain Proteins ,Regulation of gene expression ,Mice, Inbred BALB C ,Multidisciplinary ,Tumor Suppressor Proteins ,Acetylation ,Nasopharyngeal Neoplasms ,General Chemistry ,DNA Methylation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Transplantation ,stomatognathic diseases ,030104 developmental biology ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,Female ,Snail Family Transcription Factors - Abstract
Nasopharyngeal carcinoma (NPC) is characterized by a high rate of local invasion and early distant metastasis. Increasing evidence indicates that epigenetic abnormalities play important roles in NPC development. However, the epigenetic mechanisms underlying NPC metastasis remain unclear. Here we investigate aberrantly methylated transcription factors in NPC tissues, and we identify the HOP homeobox HOPX as the most significantly hypermethylated gene. Consistently, we find that HOXP expression is downregulated in NPC tissues and NPC cell lines. Restoring HOPX expression suppresses metastasis and enhances chemosensitivity of NPC cells. These effects are mediated by HOPX-mediated epigenetic silencing of SNAIL transcription through the enhancement of histone H3K9 deacetylation in the SNAIL promoter. Moreover, we find that patients with high methylation levels of HOPX exhibit poor clinical outcomes in both the training and validation cohorts. In summary, HOPX acts as a tumour suppressor via the epigenetic regulation of SNAIL transcription, which provides a novel prognostic biomarker for NPC metastasis and therapeutic target for NPC treatment., HOPX is a transcription factor epigenetically silenced in several cancers. Here the authors, by analysing methylation profiles, identify HOPX as a suppressor of metastasis in nasopharyngeal carcinoma: mechanistically HOPX inhibits SNAIL transcription through deacetylation-mediated silencing.
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- 2017
38. 中国老年患者经桡动脉与股动脉介入治疗比较
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Chen Jin, null 金辰, null 徐奕, null 乔树宾, null 唐欣然, null 吴永健, null 颜红兵, null 窦克非, null 徐波, null 杨进刚, null 杨跃进, Yi Xu, Shu-bin Qiao, Xin-ran Tang, Yong-jian Wu, Hong-bing Yan, Ke-fei Dou, Bo Xu, Jin-gang Yang, and Yue-jin Yang
- Subjects
medicine.medical_specialty ,Acute coronary syndrome ,business.industry ,Incidence (epidemiology) ,medicine.medical_treatment ,Percutaneous coronary intervention ,General Medicine ,Odds ratio ,030204 cardiovascular system & hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Statistical significance ,Conventional PCI ,Cardiology ,Retrospective analysis ,Medicine ,030212 general & internal medicine ,Myocardial infarction ,business - Abstract
Objective To compare hospital costs and clinical outcomes between transradial intervention (TRI) and transfemoral intervention (TFI) in elderly patients aged over 65 years. Methods We identified 1229 patients aged over 65 years who underwent percutaneous coronary intervention (PCI) in Fuwai Hospital, Beijing, China, between January 1 and December 31, 2010. Total hospital costs and in-hospital outcomes were compared between TRI and TFI. An inverse probability weighting (IPW) model was introduced to control potential biases. Results Patients who underwent TRI were younger, less often female, more likely to receive PCI for single-vessel lesions, and less likely to undergo the procedure for ostial lesions. TRI was associated with a cost saving of CNY7495 (95%CI: CNY4419-10 420). Such differences were mainly driven by lower PCI-related costs. TRI patients had shorter length of stay (1.9 days, 95%CI: 1.1-2.7 days), shorter post-procedural stay (0.7 days, 95%CI: 0.3-1.1 days), and fewer major adverse cardiac events (adjusted odds ratio = 0.47, 95%CI: 0.31-0.73). There was no statistical significance in the incidence of post-PCI bleeding between TRI and TFI (P>0.05). Such differences remained consistent in clinically relevant subgroups of acute myocardial infarction, acute coronary syndrome, and stable angina. Conclusion The use of TRI in patients aged over 65 years was associated with significantly reduced hospital costs and more favorable clinical outcomes.
- Published
- 2017
39. Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
- Author
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Xue Bai, Xue-Jun Guo, Jian Wang, Zhong-Yi Dong, Xin-Ran Tang, Yuan Fang, Dehua Wu, Ze-Qin Guo, Qin Zeng, Yao-Wei Zhang, Zhu Liu, Sha-Sha Du, Xiu-Ju Du, Li Liu, and Hong-Bo Zhu
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,DNA Copy Number Variations ,medicine.medical_treatment ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Randomized controlled trial ,law ,Internal medicine ,Neoplasms ,medicine ,Biomarkers, Tumor ,Humans ,Neoplasm Metastasis ,Survival rate ,Aged ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,Prognosis ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,Cohort ,Mutation ,Biomarker (medicine) ,Female ,business - Abstract
Purpose: Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu. Experimental Design: Non-ICI–treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non–small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy. Results: TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI–treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors. Conclusions: The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.
- Published
- 2019
40. Development and Validation of a Gene Mutation-Based Signature to Predict Response to PD-1 Inhibitors in Non-Squamous NSCLC: A Retrospective Multicohort Study
- Author
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Hao Sun, Xue Bai, Hong-Hong Yan, Dehua Wu, Hesan Luo, Xin-Ran Tang, Li Liu, Zhong-Yi Dong, Jian Wang, Shuai Kang, Yuhan Chen, Yuan Fang, Xiu-Ju Du, Hong-Bo Zhu, Qiang Fu, Yi-Long Wu, Chao Zhang, and Chuanhui Cao
- Subjects
Oncology ,medicine.medical_specialty ,Mutation ,business.industry ,medicine.medical_treatment ,Immunotherapy ,medicine.disease_cause ,Clinical trial ,Informed consent ,Non squamous ,Internal medicine ,Cohort ,medicine ,KRAS ,business ,Exome sequencing - Abstract
Background: Genetic variations in non-small cell lung cancer (NSCLC) have been shown potential impact on immune microenvironment, and associated with response or resistance to programmed cell death protein 1 (PD-1) blockade immunotherapy. We therefore undertook an unbiased analysis to develop a gene mutation-based signature (GMS) and predict the response to anti-PD-(L1) therapy. Methods: In this retrospective multicohort analysis, 316 patients with nonsquamous NSCLC treated with anti-PD-(L1) based therapy from three independent cohorts were included in our study. We developed a risk model named GMS based on the MSK training cohort (n=123). The predictive model was first validated in the separate internal MSK cohort (n=82), and then validated in Checkmate-012 (n=59) and Keynote/SU2C (n=52) external clinical trial cohorts. Tumor samples from the patients were molecularly profiled by MSK or whole exome sequencing. Findings: A GMS that consisted of 8 genes (TP53, KRAS, STK11, EGFR, PTPRD, KMT2C, SMAD4 and HGF) was generated to classify patients into high and low GMS groups in the training cohort. Patients with high GMS in the training cohort had longer progression-free survival (HR 0·44, 0·30-0·65, p=0·0002) and overall survival (HR 0·56, 0·33-0·94, p=0·0412) compared with low GMS. We noted equivalent findings in the internal validation cohort and in the external validation cohort. The GMS was demonstrated as an independent predictive factor for anti-PD-1(L1) therapy, without affecting the prognosis of non-squamous NSCLC. Meanwhile, GMS showed undifferentiated predictive value in patients with different clinicopathological features. Notably, both GMS and PD-L1 were independent predictors and demonstrated poorly correlated, inclusion of PD-L1 with GMS furtherly improved the predictive capacity for PD-1 blockade immunotherapy. Interpretation: Our study highlights the potential predictive value of GMS for immunotherapeutic benefit in non-squamous NSCLC. Besides, the combination of GMS and PD-L1 may serve as optimal partner in guiding treatment decisions for anti-PD-(L1) based therapy. Funding Statement: The National Natural Science Foundation for Young Scientists of China, the Natural Science Foundation of Guangdong Province, and the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University. Declaration of Interests: The authors have no actual or potential conflicts of interest to declare. Ethics Approval Statement: This study was approved by the Institutional Ethical Review Boards of Nanfang Hospital. Patients provided signed informed consent in accordance with their respective trial protocols or MSK-IMPACT sequencing project.
- Published
- 2019
41. miR-16 targets fibroblast growth factor 2 to inhibit NPC cell proliferation and invasion via PI3K/AKT and MAPK signaling pathways
- Author
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Xiao-Jing Yang, Na Liu, Ya-Qin Wang, Qingmei He, Jiewei Chen, Xin-Ran Tang, Ying-Qin Li, Jun Ma, Xin Wen, Jian Zhang, and Xianyue Ren
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Lung Neoplasms ,Carcinogenesis ,Fibroblast growth factor ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,miR-16 ,Mice, Inbred BALB C ,Nasopharyngeal Carcinoma ,Gene Expression Regulation, Neoplastic ,tumor growth ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Mitogen-Activated Protein Kinases ,Signal transduction ,Research Paper ,MAP Kinase Signaling System ,Nasopharyngeal neoplasm ,Mice, Nude ,03 medical and health sciences ,Cell Line, Tumor ,otorhinolaryngologic diseases ,medicine ,metastasis ,Animals ,Humans ,Neoplasm Invasiveness ,fibroblast growth factor 2 ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Cell growth ,business.industry ,Carcinoma ,Nasopharyngeal Neoplasms ,Genetic Therapy ,medicine.disease ,Xenograft Model Antitumor Assays ,MicroRNAs ,stomatognathic diseases ,030104 developmental biology ,Nasopharyngeal carcinoma ,Immunology ,Cancer research ,Neoplasm Recurrence, Local ,business ,Proto-Oncogene Proteins c-akt - Abstract
Dysregulation of miRNAs has been shown to contribute to the carcinogenesis and progression of nasopharyngeal carcinoma (NPC). Our previous microarray data showed that miR-16 expression is significantly decreased in archived NPC tissues. Here, we confirmed that miR-16 was reduced in NPC cell lines and freshly-frozen samples. Ectopic expression of miR-16 suppressed NPC cell proliferation, migration, and invasion in vitro and inhibited tumor growth and metastatic colonization in the lung in vivo. Furthermore, fibroblast growth factor 2 (FGF2) was identified as a direct target of miR-16, and both phosphoinositide-3- kinase/AKT (PI3K/AKT) and mitogen-activated protein kinase (MAPK) signaling pathways were repressed after miR-16 overexpression. In addition, the restoration of FGF2 reversed the suppressive effects of miR-16. Together, these results indicated that miR-16 suppresses NPC carcinogenesis and progression by targeting FGF2, thereby representing a potential target for miRNA-based therapy for NPC in the future.
- Published
- 2015
42. Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC
- Author
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Xin-Ran Tang, Jun Ma, Qing Mei He, Guan Qun Zhou, Xiao-Jing Yang, Ying Qin Li, Na Liu, Xian Yue Ren, Wei Jiang, Ying Sun, Ya Fei Xu, and Xin Wen
- Subjects
Adult ,Male ,Cancer Research ,Blotting, Western ,Nasopharyngeal neoplasm ,Kaplan-Meier Estimate ,Biology ,Transfection ,medicine.disease_cause ,Polymerase Chain Reaction ,Disease-Free Survival ,Metastasis ,Mice ,Cyclin D1 ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,RNA, Small Interfering ,Wnt Signaling Pathway ,Proportional Hazards Models ,Regulation of gene expression ,Mice, Inbred BALB C ,Nasopharyngeal Carcinoma ,Cell growth ,Carcinoma ,Wnt signaling pathway ,Membrane Proteins ,Nasopharyngeal Neoplasms ,Middle Aged ,Prognosis ,medicine.disease ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,stomatognathic diseases ,Oncology ,Nasopharyngeal carcinoma ,Immunology ,Cancer research ,Heterografts ,Intercellular Signaling Peptides and Proteins ,Female ,Carcinogenesis - Abstract
Distant metastasis remains the predominant mode of treatment failure in nasopharyngeal carcinoma (NPC). Unfortunately, the molecular events underlying NPC metastasis remain poorly understood. Secreted frizzled-related protein 1 (SFRP1) plays an important role in tumorigenesis and progression. However, little is known about the function and mechanism of SFRP1 in NPC. Immunohistochemistry was used to determine SFRP1 expression levels in patients with NPC. SFRP1 function was evaluated using MTT, colony formation, wound-healing, Transwell assays, and in vivo models. The methylation level of SFRP1 in NPC cells was examined using bisulfate pyrosequencing; the Wnt/β-catenin signaling pathway genes were studied using Western blotting. Compared with patients with high SFRP1 expression, patients with low SFRP1 expression had worse overall survival [HR, 2.32; 95% confidence interval (CI), 1.36–3.94; P = 0.002], disease-free survival (HR, 1.98; 95% CI, 1.23–3.18; P = 0.005), and distant metastasis-free survival (HR, 2.07; 95% CI, 1.19–3.59; P = 0.009). Multivariate Cox regression analysis indicated that SFRP1 was an independent prognostic factor. Furthermore, SFRP1 was significantly downregulated in NPC cell lines. SFRP1 overexpression suppressed NPC cell proliferation, migration, and invasion in vitro and lung colonization in vivo. SFRP1 expression was restored after treatment with a demethylation agent, and the SFRP1 promoter region was hypermethylated in NPC cells. β-Catenin, c-Myc, and cyclin D1 were downregulated after SFRP1 restoration, which suggested that SFRP1 suppressed growth and metastasis by inhibiting the Wnt/β-catenin signaling pathway in NPC. SFRP1 provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment. Cancer Prev Res; 8(10); 968–77. ©2015 AACR.
- Published
- 2015
43. Development and Validation of a Prognostic Nomogram Based on Residual Tumor in Patients With Nondisseminated Nasopharyngeal Carcinoma
- Author
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Zhu-Liu, Xin-Ran Tang, Dehua Wu, Ping-Yan Liao, Chan-Tao Huang, Guan-Dong Liu, and Zhong-Yi Dong
- Subjects
Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Neoplasm, Residual ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Clinical Decision-Making ,Kaplan-Meier Estimate ,Residual ,lcsh:RC254-282 ,nomogram ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,In patient ,Progression-free survival ,residual tumor ,Retrospective Studies ,Nasopharyngeal Carcinoma ,medicine.diagnostic_test ,business.industry ,Nasopharyngeal Neoplasms ,Magnetic resonance imaging ,Middle Aged ,Nomogram ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Magnetic Resonance Imaging ,Progression-Free Survival ,Survival Rate ,Nomograms ,030104 developmental biology ,Oncology ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Original Article ,Female ,Radiology ,Neoplasm Recurrence, Local ,business - Abstract
Objectives: To investigate the prognostic value of residual tumor based on Magnetic resonance imaging(MRI) and establish an effective prognostic nomogram model referring to clinical,pathological and other related factors for predicting prognosis in nasopharyngeal carcinoma. Methods: Overall, 538 patients with non-metastatic, histologically-confirmed nasopharyngeal carcinoma were retrospectively examined. Data from 397 patients were used for the construction and validation of a nomogram based on the presence of residual tumor. A concordance index (C-index) was employed to assess the predictive accuracy and discriminative ability of the nomogram. Results: The 3-year survival rates in the non-residual and residual tumor cohorts were as follows: progression-free survival, 73.4% vs. 61.0%, P = 0.009; locoregional recurrence-free survival, 81.9% vs. 72.0%, P = 0.02; and distant metastasis-free survival, 80.7% vs. 73.5%, P = 0.11. Nine significant factors were included in the nomogram model. The calibration curve for the probability of progression-free survival showed that the nomogram-based predictive values had good concordance with the actual observations. Conclusion: The results showed that the patients in the residual tumor cohorts had a worse prognosis.The proposed nomogram may predict the prognosis and guide clinical decision-making concerning local residual tumors in nasopharyngeal carcinoma patients. Patients with a high risk of progression require more timely and aggressive treatment.
- Published
- 2020
44. EZH2-DNMT1-mediated epigenetic silencing of miR-142-3p promotes metastasis through targeting ZEB2 in nasopharyngeal carcinoma
- Author
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Pan-Pan Zhang, Xiao-Jing Yang, Na Liu, Xin Wen, Jun Ma, Ya-Qin Wang, Qingmei He, Xiao-Hong Hong, Ying Sun, Ying-Qin Li, Yuan Lei, Jian Zhang, and Xin-Ran Tang
- Subjects
0301 basic medicine ,DNA (Cytosine-5-)-Methyltransferase 1 ,Cell ,Biology ,Article ,Metastasis ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,medicine ,otorhinolaryngologic diseases ,Gene silencing ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Epigenetics ,Gene Silencing ,Molecular Biology ,Cells, Cultured ,Oligonucleotide Array Sequence Analysis ,Zinc Finger E-box Binding Homeobox 2 ,Nasopharyngeal Carcinoma ,EZH2 ,Nasopharyngeal Neoplasms ,Cell Biology ,medicine.disease ,stomatognathic diseases ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,DNA methylation ,DNMT1 ,Cancer research - Abstract
Human nasopharyngeal carcinoma (NPC) has the highest metastatic rate in head and neck. However, the mechanisms underlying NPC metastasis remain unclear. Here using propensity-score-matched miRNA microarray analysis, miR-142-3p is identified to be the most correlated with distant-metastasis-free survival and downregulated in paraffin-embedded NPC with distant metastasis, which is validated in both internal cohort and external GEO dataset from Canada. miR-142 locus hypermethylation was observed and found to be associated with miR-142-3p downregulation in metastatic NPC. Furthermore, miR-142-3p was epigenetically silenced by EZH2-recruited DNMT1 and suppressed NPC cell metastasis and EMT. Intersecting PCR array gene profiling with bioinformatic prediction, we identify ZEB2 as a direct and functional target of miR-142-3p in NPC. Reversal of miR-142-3p silencing efficiently suppresses NPC cell invasion and metastasis. Moreover, epigenetic miR-142 hypermethylation is correlated with unfavorable prognosis in both training and validation cohorts. This study identifies miR-142-3p as a key suppressive regulator in NPC metastasis and reveals a DNMT1-mediated epigenetic mechanism for miR-142-3p silencing, providing a potential prognostic marker and therapeutic target to combat NPC metastasis.
- Published
- 2018
45. Hypermethylation of
- Author
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Jian, Zhang, Ying-Qin, Li, Rui, Guo, Ya-Qin, Wang, Pan-Pan, Zhang, Xin-Ran, Tang, Xin, Wen, Xiao-Hong, Hong, Yuan, Lei, Qing-Mei, He, Xiao-Jing, Yang, Ying, Sun, Jun, Ma, and Na, Liu
- Subjects
Mice, Inbred BALB C ,Protein Stability ,Intracellular Signaling Peptides and Proteins ,Down-Regulation ,Membrane Proteins ,Mice, Nude ,Apoptosis ,Nasopharyngeal Neoplasms ,DNA Methylation ,Prognosis ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Mice ,Cell Movement ,Lymphatic Metastasis ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Female ,Apoptosis Regulatory Proteins ,Cell Proliferation ,Signal Transduction - Abstract
Altered DNA methylation is a key feature of cancer, and aberrant methylation is important in nasopharyngeal carcinoma (NPC) development. However, the methylation mechanisms underlying metastasis of NPC remain unclear. Analyzing data from public databases and conducting our own experiments, we report here that promoter hypermethylation of
- Published
- 2018
46. Differential genome-wide profiling of alternative polyadenylation sites in nasopharyngeal carcinoma by high-throughput sequencing
- Author
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Ying Sun, Na Liu, Xin Wen, Jun Ma, Qing Mei He, Ying Qing Li, Ling Long Tang, Xiao-Jing Yang, Ya Fei Xu, and Xin-Ran Tang
- Subjects
0301 basic medicine ,Polyadenylation ,Protein catabolic process ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,education ,lcsh:Medicine ,Macromolecule catabolic process ,Computational biology ,Biology ,DNA sequencing ,03 medical and health sciences ,mental disorders ,medicine ,Humans ,Pharmacology (medical) ,Ligase activity ,Molecular Biology ,Gene ,Regulation of gene expression ,Nasopharyngeal Carcinoma ,High-throughput sequencing ,Gene Expression Profiling ,Research ,Biochemistry (medical) ,lcsh:R ,High-Throughput Nucleotide Sequencing ,Alternative polyadenylation ,Nasopharyngeal Neoplasms ,Cell Biology ,General Medicine ,medicine.disease ,Genome-wide profiling ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Nasopharyngeal carcinoma ,psychological phenomena and processes - Abstract
Background Alternative polyadenylation (APA) is a widespread phenomenon in the posttranscriptional regulation of gene expression that generates mRNAs with alternative 3′-untranslated regions (3’UTRs). APA contributes to the pathogenesis of various diseases, including cancer. However, the potential role of APA in the development of nasopharyngeal carcinoma (NPC) remains largely unknown. Methods A strategy of sequencing APA sites (SAPAS) based on second-generation sequencing technology was carried out to explore the global patterns of APA sites and identify genes with tandem 3’UTRs in samples from 6 NPC and 6 normal nasopharyngeal epithelial tissue (NNET). Sequencing results were then validated using quantitative RT-PCR in a larger cohort of 16 NPC and 16 NNET samples. Results The sequencing data showed that the use of tandem APA sites was prevalent in NPC, and numerous genes with APA-switching events were discovered. In total, we identified 195 genes with significant differences in the tandem 3’UTR length between NPC and NNET; including 119 genes switching to distal poly (A) sites and 76 genes switching to proximal poly (A) sites. Several gene ontology (GO) terms were enriched in the list of genes with switched APA sites, including regulation of cell migration, macromolecule catabolic process, protein catabolic process, proteolysis, small conjugating protein ligase activity, and ubiquitin-protein ligase activity. Conclusions APA site-switching events are prevalent in NPC. APA-mediated regulation of gene expression may play an important role in the development of NPC, and more detailed studies targeting genes with APA-switching events may contribute to the development of novel future therapeutic strategies for NPC. Electronic supplementary material The online version of this article (10.1186/s12929-018-0477-6) contains supplementary material, which is available to authorized users.
- Published
- 2018
47. Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and tumorigenicity in nasopharyngeal carcinoma by inhibiting cell cycle arrest
- Author
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Xiao-Jing Yang, Ying Qin Li, Pan Pan Zhang, Jun Ma, Qing Mei He, Ya Qin Wang, Na Liu, Xin Wen, Jian Zhang, Ying Sun, and Xin-Ran Tang
- Subjects
0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,Proliferation ,Down-Regulation ,Biology ,lcsh:RC254-282 ,Epigenesis, Genetic ,ZNF671 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cyclin D1 ,Downregulation and upregulation ,Cell Line, Tumor ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Gene silencing ,Gene Regulatory Networks ,Hypermethylation ,Cell Proliferation ,Zinc finger ,Tumorigenicity ,Nasopharyngeal Carcinoma ,Cell growth ,Research ,Tumor Suppressor Proteins ,Carcinoma ,High-Throughput Nucleotide Sequencing ,Correction ,Nasopharyngeal Neoplasms ,Cell Cycle Checkpoints ,Sequence Analysis, DNA ,DNA Methylation ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Molecular biology ,Gene Expression Regulation, Neoplastic ,stomatognathic diseases ,030104 developmental biology ,Oncology ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,Neoplasm Transplantation - Abstract
Background Epigenetic abnormalities play important roles in nasopharyngeal cancer (NPC), however, the epigenetic changes associated with abnormal cell proliferation remain unclear. Methods We detected epigenetic change of ZNF671 in NPC tissues and cell lines by bisulfite pyrosequencing. We evaluated zinc finger protein 671 (ZNF671) expression in NPC cell lines and clinical tissues using real-time PCR and western blotting. Then, we established NPC cell lines that stably overexpressed ZNF671 and knocked down ZNF671 expression to explore its function in NPC in vitro and in vivo. Additionally, we investigated the potential mechanism of ZNF671 by identifying the mitotic spindle and G2/M checkpoint pathways pathway downstream genes using gene set enrichment analysis, flow cytometry and western blotting. Results ZNF671 was hypermethylated in NPC tissues and cell lines. The mRNA and protein expression of ZNF671 was down-regulated in NPC tissues and cell lines and the mRNA expression could be upregulated after the demethylation agent 5-aza-2′-deoxycytidine treatment. Overexpression of ZNF671 suppressed NPC cell proliferation and colony formation in vitro; silencing ZNF671 using a siRNA had the opposite effects. Additionally, overexpression of ZNF671 reduced the tumorigenicity of NPC cells in xenograft model in vivo. The mechanism study determined that overexpressing ZNF671 induced S phase arrest in NPC cells by upregulating p21 and downregulating cyclin D1 and c-myc. Conclusions Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and enhances tumorigenicity by inhibiting cell cycle arrest in NPC, which may represent a novel potential therapeutic target.
- Published
- 2017
48. Prognostic significance of tumor-infiltrating lymphocytes in nondisseminated nasopharyngeal carcinoma: A large-scale cohort study
- Author
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Ya-Qin, Wang, Yu-Pei, Chen, Yu, Zhang, Wei, Jiang, Na, Liu, Jing-Ping, Yun, Ying, Sun, Qing-Mei, He, Xin-Ran, Tang, Xin, Wen, Xiao-Jing, Yang, Pan-Pan, Zhang, Jian, Zhang, Yuan, Lei, Ying-Qin, Li, and Jun, Ma
- Subjects
Adult ,Cohort Studies ,Male ,Lymphocytes, Tumor-Infiltrating ,Nasopharyngeal Carcinoma ,Humans ,Female ,Kaplan-Meier Estimate ,Middle Aged ,Prognosis ,Progression-Free Survival ,Aged ,Proportional Hazards Models - Abstract
The American Joint Committee on Cancer (AJCC) staging system is inadequate for an accurate prognosis in nasopharyngeal carcinoma (NPC). Thus, new biomarkers are under intense investigation. Here, we investigated whether the density of TILs could predict prognosis in NPC. First, we used 1490 cases of nasopharyngeal carcinoma samples from two independent cohorts to evaluate the density and distribution of tumor-infiltrating lymphocytes (TILs). Second, in one cohort, we assessed associations between TILs and clinical outcomes in 593 randomly selected samples (defined as the training set) and validated findings in the remaining 593 samples (defined as the validation set). Furthermore, we confirmed the prognostic value of TILs in a second independent cohort of 304 cases (defined as the independent set). Based on multivariable Cox regression analysis, we also established an effective prognostic nomogram including TILs to improve accuracy in predicting disease-free survival (DFS) for patients with nondisseminated NPC. We found that high TILs in the training set were significantly associated with favorable DFS [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.28-0.58, p 0.001], overall survival (OS, HR 0.42, 95% CI 0.27-0.64, p 0.001), distant metastasis-free survival (DMFS, HR 0.37, 95% CI 0.23-0.58, p 0.001) and local-regional recurrent free survival (LRRFS, HR 0.43, 95% CI 0.25-0.73, p = 0.002). Multivariate analysis showed that TILs are an independent prognostic indicator for DFS in all cohorts. In summary, this study indicated that TILs may reflect the immunological heterogeneity of NPC and could represent a new prognostic biomarker.
- Published
- 2017
49. Transradial Versus Transfemoral Approach for Percutaneous Coronary Intervention in Elderly Patients in China: A Retrospective Analysis
- Author
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Chen, Jin, Yi, Xu, Shu-Bin, Qiao, Xin-Ran, Tang, Yong-Jian, Wu, Hong-Bing, Yan, Ke-Fei, Dou, Bo, Xu, Jin-Gang, Yang, and Yue-Jin, Yang
- Subjects
Male ,China ,Percutaneous Coronary Intervention ,Sex Factors ,Age Factors ,Myocardial Infarction ,Humans ,Female ,Hospital Costs ,Aged ,Retrospective Studies - Abstract
Objective To compare hospital costs and clinical outcomes between transradial intervention (TRI) and transfemoral intervention (TFI) in elderly patients aged over 65 years. Methods We identified 1229 patients aged over 65 years who underwent percutaneous coronary intervention (PCI) in Fuwai Hospital, Beijing, China, between January 1 and December 31, 2010. Total hospital costs and in-hospital outcomes were compared between TRI and TFI. An inverse probability weighting (IPW) model was introduced to control potential biases. Results Patients who underwent TRI were younger, less often female, more likely to receive PCI for single-vessel lesions, and less likely to undergo the procedure for ostial lesions. TRI was associated with a cost saving of CNY7495 (95%CI: CNY4419-10 420). Such differences were mainly driven by lower PCI-related costs. TRI patients had shorter length of stay (1.9 days, 95%CI: 1.1-2.7 days), shorter post-procedural stay (0.7 days, 95%CI: 0.3-1.1 days), and fewer major adverse cardiac events (adjusted odds ratio = 0.47, 95%CI: 0.31-0.73). There was no statistical significance in the incidence of post-PCI bleeding between TRI and TFI (P0.05). Such differences remained consistent in clinically relevant subgroups of acute myocardial infarction, acute coronary syndrome, and stable angina. Conclusion The use of TRI in patients aged over 65 years was associated with significantly reduced hospital costs and more favorable clinical outcomes.
- Published
- 2017
50. Abstract 4065: Prognostic and predictive role of tumor mutation burden and copy number alterations across metastatic cancer: Immunotherapeutic implications
- Author
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Dehua Wu, Xin-Ran Tang, and Zhong Yi Dong
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,SCNA ,Head and neck squamous-cell carcinoma ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,Cancer immunotherapy ,Internal medicine ,Cohort ,Cutaneous melanoma ,medicine ,Rectal Adenocarcinoma ,business ,030215 immunology - Abstract
Background: Cancer immunotherapy has provided durable responses and improved survival in a subset of patients with advanced disease. Tumor mutation burden (TMB) and copy number alterations (CNA) have been shown to be associated with response to immune checkpoint inhibitors (ICI). However, the prognostic and predictive role of TMB and CNA across different types of advanced cancer has not yet been clarified. Methods: We analyzed the prognostic value of TMB and CNA respectively and in combination across different types of advanced cancers from MSK-IMPACT sequencing cohort. For predictive analysis, non-small cell lung cancer (NSCLC, n=240) and skin cutaneous melanoma (SKCM, n=174) patients from previous studies were analyzed for efficacy to ICIs by TMB and CNA respectively and in combination. Kaplan-Meier curve and log-rank tests were used to estimate correlations of these molecular classifiers with progression-free survival (PFS), and overall survival (OS). Findings: Patients with low TMB level had longer OS in most cancer types including NSCLC, head and neck squamous cell carcinoma (HNSCC), colon and rectal adenocarcinoma (COAD) and prostate adenocarcinoma (PRAD) compared with patients with high TMB level. Similarly, patients with low CNA level had longer OS in most cancer types including NSCLC, bladder urothelial carcinoma (BLCA), breast cancer (BRCA), PRAD and glioblastoma (GBM) compared with patients with high CNA level as well. Furthermore, the combination of TMB and CNA level could serve as a better prognosis biomarker in almost all of the cancer types above. In predictive cohort, high TMB (p=0.009) level and low SCNA (p=0.052) level was associated with longer PFS in NSCLC patients receiving anti-PD1/L1 treatment respectively. For SKCM cohort, patients with low CNA level (p Interpretation: This study shows that TMB and CNA represent both a prognostic and predictive factor of outcomes. Furthermore, the combination of TMB and CNA can jointly stratify metastatic cancers into groups with different prognosis and clinical responses to ICI treatment. It might guide immunotherapeutic decisions for patients with metastatic cancer. Citation Format: Xin-Ran Tang, Zhong Yi Dong, Dehua Wu. Prognostic and predictive role of tumor mutation burden and copy number alterations across metastatic cancer: Immunotherapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4065.
- Published
- 2019
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