Anti-CD79A monoclonal antibody, clone NI25-2

Background: It has been suggested that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to chemotherapy. We aimed to validate these subtypes in several clinical cohorts and identify signature immunohistochemicalmarkers thatwould permit simple and cost-effective classification of the disease in primary care centers. Methods: Weanalyzed genomic expression profiles of bladder cancer in three cohorts of fresh frozen tumor samples: MD Anderson (n=132), Lund (n=308), and The Cancer Genome Atlas (TCGA) (n=408) to validate the expression signatures of luminal and basal subtypes and relate them to clinical follow-up data. We also used an MD Anderson cohort of archival bladder tumor samples (n=89) and a parallel tissue microarray to identify immunohistochemical markers that permitted the molecular classification of bladder cancer. Findings: Bladder cancers could be assigned to two candidate intrinsic molecular subtypes referred to here as luminal and basal in all of the datasets analyzed. Luminal tumors were characterized by the expression signature similar to the intermediate/superficial layers of normal urothelium. They showed the upregulation of PPAR. target genes and the enrichment for FGFR3, ELF3, CDKN1A, and TSC1 mutations. In addition, luminal tumors were characterized by the overexpression of E-Cadherin, HER2/3, Rab-25, and Src. Basal tumors showed the expression signature similar to the basal layer of normal urothelium. They showed the upregulation of p63 target genes, the enrichment for TP53 and RB1 mutations, and overexpression of CD49, Cyclin B1, and EGFR. Survival analyses showed that the muscle-invasive basal bladder cancers were more aggressive when compared to luminal cancers. The immunohistochemical expressions of only two markers, luminal (GATA3) and basal (KRT5/6), were sufficient to identify the molecular subtypes of bladder cancer with over 90% accuracy. Interpretation: The molecular subtypes of bladder cancer have distinct clinical behaviors and sensitivities to chemotherapy, and a simple two-marker immunohistochemical classifier can be used for prognostic and therapeutic stratification. Funding: U.S. National Cancer Institute and National Institute of Health. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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.