Person: Shen, Sipeng
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Shen
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Sipeng
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Shen, Sipeng
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Publication A multi‐omic study reveals BTG2 as a reliable prognostic marker for early‐stage non‐small cell lung cancer(John Wiley and Sons Inc., 2018) Shen, Sipeng; Zhang, Ruyang; Guo, Yichen; Loehrer, Elizabeth; Wei, Yongyue; Zhu, Ying; Yuan, Qianyu; Moran, Sebastian; Fleischer, Thomas; Bjaanæs, Maria M.; Karlsson, Anna; Planck, Maria; Staaf, Johan; Helland, Åslaug; Esteller, Manel; Su, Li; Chen, Feng; Christiani, DavidB‐cell translocation gene 2 (BTG2) is a tumour suppressor protein known to be downregulated in several types of cancer. In this study, we investigated a potential role for BTG2 in early‐stage non‐small cell lung cancer (NSCLC) survival. We analysed BTG2 methylation data from 1230 early‐stage NSCLC patients from five international cohorts, as well as gene expression data from 3038 lung cancer cases from multiple cohorts. Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumour tissues were associated with lower overall survival. The prognostic model based on methylation could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51–2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 expression was positively correlated with survival in each cohort (HR range, 0.28–0.68), which we confirmed with meta‐analysis (HR = 0.61, 95% CI 0.54–0.68). The three CpG probes were all negatively correlated with BTG2 expression. Importantly, an integrative model of BTG2 methylation, expression and clinical information showed better predictive ability in the training set and validation set. In conclusion, the methylation and integrated prognostic signatures based on BTG2 are stable and reliable biomarkers for early‐stage NSCLC. They may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future.Publication Mutant-allele fraction heterogeneity is associated with non-small cell lung cancer patient survival(D.A. Spandidos, 2018) Shen, Sipeng; Wei, Yongyue; Zhang, Ruyang; Du, Mulong; Duan, Weiwei; Yang, Sheng; Zhao, Yang; Christiani, David; Chen, FengGenetic intratumor heterogeneity is associated with tumor occurrence, development and overall outcome. The present study aims to explore the association between mutant-allele fraction (MAF) heterogeneity and patient overall survival in lung cancer. Somatic mutation data of 939 non-small cell lung cancer (NSCLC) cases were obtained from The Cancer Genome Atlas. Entropy-based mutation allele fraction (EMAF) score was used to describe the uncertainty of individual somatic mutation patterns and to further analyze the association with patient overall survival. Results indicated that association between EMAF and overall survival was significant in the discovery set [hazard ratio (H)R=1.62; 95% confidence interval (CI): 1.08–2.41; P=0.018] and replication set (HR=1.63; 95% CI: 1.11–2.37; P=0.011). In addition, EMAF was also significantly different in lung adenocarcinoma and squamous cell carcinoma. Furthermore, a significant difference was indicated in early-stage patients. Results from c-index analysis indicated that EMAF improved the model predictive performance on the 3-year survival beyond that of traditional clinical staging, particularly in early-stage patients. In conclusion, EMAF successfully reflected MAF heterogeneity among patients with NSCLC. Additionally, EMAF improved the predictive performance in early-stage patient prognosis beyond that of traditional clinical staging. In clinical application, EMAF appears to identify a subset of early-stage patients with a poor prognosis and therefore may help inform clinical decisions regarding the application of chemotherapy after surgery.Publication Seven-CpG-based prognostic signature coupled with gene expression predicts survival of oral squamous cell carcinoma(BioMed Central, 2017) Shen, Sipeng; Wang, Guanrong; Shi, Qianwen; Zhang, Ruyang; Zhao, Yang; Wei, Yongyue; Chen, Feng; Christiani, DavidBackground: DNA methylation has started a recent revolution in genomics biology by identifying key biomarkers for multiple cancers, including oral squamous cell carcinoma (OSCC), the most common head and neck squamous cell carcinoma. Methods: A multi-stage screening strategy was used to identify DNA-methylation-based signatures for OSCC prognosis. We used The Cancer Genome Atlas (TCGA) data as training set which were validated in two independent datasets from Gene Expression Omnibus (GEO). The correlation between DNA methylation and corresponding gene expression and the prognostic value of the gene expression were explored as well. Results: The seven DNA methylation CpG sites were identified which were significantly associated with OSCC overall survival. Prognostic signature, a weighted linear combination of the seven CpG sites, successfully distinguished the overall survival of OSCC patients and had a moderate predictive ability for survival [training set: hazard ratio (HR) = 3.23, P = 5.52 × 10−10, area under the curve (AUC) = 0.76; validation set 1: HR = 2.79, P = 0.010, AUC = 0.67; validation set 2: HR = 3.69, P = 0.011, AUC = 0.66]. Stratification analysis by human papillomavirus status, clinical stage, age, gender, smoking status, and grade retained statistical significance. Expression of genes corresponding to candidate CpG sites (AJAP1, SHANK2, FOXA2, MT1A, ZNF570, HOXC4, and HOXB4) was also significantly associated with patient’s survival. Signature integrating of DNA methylation, gene expression, and clinical information showed a superior ability for prognostic prediction (AUC = 0.78). Conclusion: Prognostic signature integrated of DNA methylation, gene expression, and clinical information provides a better prognostic prediction value for OSCC patients than that with clinical information only. Electronic supplementary material The online version of this article (doi:10.1186/s13148-017-0392-9) contains supplementary material, which is available to authorized users.Publication Epigenetic modifications in KDM lysine demethylases associate with survival of early-stage NSCLC(BioMed Central, 2018) Wei, Yongyue; Liang, Junya; Zhang, Ruyang; Guo, Yichen; Shen, Sipeng; Su, Li; Lin, Xihong; Moran, Sebastian; Helland, Åslaug; Bjaanæs, Maria M.; Karlsson, Anna; Planck, Maria; Esteller, Manel; Fleischer, Thomas; Staaf, Johan; Zhao, Yang; Chen, Feng; Christiani, DavidBackground: KDM lysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations in KDM genes and their roles in lung cancer survival. Methods: Tumor tissue samples of 1230 early-stage non-small cell lung cancer (NSCLC) patients were collected from the five independent cohorts. The 393 methylation sites in KDM genes were extracted from epigenome-wide datasets and analyzed by weighted random forest (Ranger) in discovery phase and validation dataset, respectively. The variable importance scores (VIS) for the sites in top 5% of both discovery and validation sets were carried forward for Cox regression to further evaluate the association with patient’s overall survival. TCGA transcriptomic data were used to evaluate the correlation with the corresponding DNA methylation. Results: DNA methylation at sites cg11637544 in KDM2A and cg26662347 in KDM1A were in the top 5% of VIS in both discovery phase and validation for squamous cell carcinomas (SCC), which were also significantly associated with SCC survival (HRcg11637544 = 1.32, 95%CI, 1.16–1.50, P = 1.1 × 10−4; HRcg26662347 = 1.88, 95%CI, 1.37–2.60, P = 3.7 × 10−3), and correlated with corresponding gene expression (cg11637544 for KDM2A, P = 1.3 × 10−10; cg26662347 for KDM1A P = 1.5 × 10−5). In addition, by using flexible criteria for Ranger analysis followed by survival classification tree analysis, we identified four clusters for adenocarcinomas and five clusters for squamous cell carcinomas which showed a considerable difference of clinical outcomes with statistical significance. Conclusions: These findings highlight the association between somatic DNA methylation in KDM genes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets. Electronic supplementary material The online version of this article (10.1186/s13148-018-0474-3) contains supplementary material, which is available to authorized users.