Discovery and validation of DNA methylation markers for overall survival prognosis in patients with thymic epithelial tumors
CLINICAL EPIGENETICS
Authors: Li, Songlin; Yuan, Yuan; Xiao, He; Dai, Jiajia; Ye, Yunfei; Zhang, Qin; Zhang, Zhimin; Jiang, Yuhan; Luo, Jia; Hu, Jing; Chen, Chuan; Wang, Ge
Abstract
BackgroundThe current prognosis of thymic epithelial tumors (TETs) is according to the World Health Organization (WHO) histologic classification and the Masaoka staging system. These methods of prognosis have certain limitations in clinical application and there is a need to seek new method for determining the prognosis of patients with TETs. To date, there have been no studies done on the use of DNA methylation biomarkers for prognosis of TETs. The present study was therefore carried out to identify DNA methylation biomarkers that can determine the overall survival in patients with TETs.MethodsBioinformatic analysis of TCGA 450K methylation array data, transcriptome sequencing data, WHO histologic classification and Masaoka staging system was performed to identify differentially expressed methylation sites between thymoma and thymic carcinoma as well as the different DNA methylation sites associated with the overall survival in patients with TETs. Using pyrosequencing, 4 different methylation sites (cg05784862, cg07154254, cg02543462, and cg06288355) were sequenced from tumor tissues of 100 Chinese patients with TETs. A prognostic model for TETs was constructed using these four methylation sites.ResultsThe TCGA dataset showed 5155 and 6967 hyper- and hypomethylated CpG sites in type A-B3 group and type C group, respectively, of which 3600 were located within the gene promoter regions. One hundred thirty-four genes were silenced by promoter hypermethylation and 174 mRNAs were upregulated. Analysis of univariate and multivariate Cox regression showed significant association between the methylation levels of 187 sites and the overall survival in patients with TETs. cg05784862(KSR1), cg07154254(ELF3), cg02543462(ILRN), and cg06288355(RAG1) were identified as independent prognostic factors for overall survival in patients with TETs after adjusting for Masaoka staging in 100 Chinese patients. The prognostic model which consists of the four abovementioned genes had higher accuracy for predicting the 5-year overall survival in patients with TETs as compared to the Masaoka clinical staging. (Time-dependent ROC analysis AUC 1.000 vs 0.742, P=2.7x10(-6)).ConclusionsThe methylation levels of cg05784862(KSR1), cg07154254(ELF3), cg02543462(ILRN), and cg06288355(RAG1) sites are associated with the progression of TETs and may serve as new biomarkers for predicting the overall survival in patients with TETs.
Second-line therapies in advanced biliary tract cancers
LANCET ONCOLOGY
Authors: Tella, Sri Harsha; Kommalapati, Anuhya; Borad, Mitesh J.; Mahipal, Amit
Abstract
Biliary tract cancers constitute approximately 3% of gastrointestinal malignancies with poor prognosis. Surgical therapy is the main form of treatment in localised disease; however, for patients with advanced stage or unresectable disease, locoregional and systemic chemotherapeutics are primary treatment options. Although the combination of gemcitabine and cisplatin is a standard regimen of choice, there are no consensus guidelines that help in choosing an appropriate second-line therapy. Substantial progress has been made in the past decade to understand the tumorigenesis and genetic landscape of each biliary tract cancer subtype, which facilitates precision medicine for this cancer. Common genes implicated in biliary tract cancer tumorigenesis include IDH1, IDH2, FGFR1, FGFR2, FGFR3, EPHA2, BAP1, ARID1B, ELF3, PBRM1, PRKACA, PRKACB, HER2, and BRAF. With the advancements in molecular pathogenesis of biliary tract cancer, especially in an era of personalised medicine, many questions are yet to be answered in advanced stages of the cancer: what subset of patients might benefit from second-line drugs, how to choose an optimal second-line regimen, and their effects on quality of life. This Review seeks to summarise available literature and discuss the potential second-line systemic therapy options for advanced biliary tract cancer on the basis of advancements of our knowledge on molecular pathogenesis and tumorigenesis.