Anti-PLEC monoclonal antibody

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide with poor prognosis. Thus, identification of predictive biomarkers for early diagnosis and intervention is needed to improve patients' survival. Research shows that heritable mutations, such as single nucleotide polymorphisms (SNPs), contribute to human cancer susceptibility significantly. However, the association of copy number variations (CNVs), another major source of genetic variation, with ESCC risk remains poorly clarified. In this study, we aimed to identify ESCC risk-related CNVs based on candidate-gene strategy in a case-control study. A meta-analysis was first performed to identify the most variable chromosome regions of ESCC tissues. Bioinformatic analysis and dual-luciferase reporter assays were carried out to evaluate the properties of all recorded CNVs located on these regions. Six candidate CNVs located within well-known oncogenes and detoxification-associated enzymes were enrolled in the final analysis. A newly developed multiplex gene copy number quantitation method AccuCopy (TM) was employed to simultaneously genotype all six candidate sites in 404 ESCC patients and 402 cancer-free controls from Southwest China, and in 42 ESCC tissues. qRT-PCR was performed to measure UGT2B28 mRNA in cancerous and corresponding normal tissues. Unconditional logistic regression was applied to test association between germline CNV genotypes and ESCC risk. Relationship between germline copy number variation and somatic copy number alterations was further analyzed. Finally we found that copy number loss of UDP-glucuronosyltransferase family 2, polypeptide B28 (UGT2B28) and gain of plectin (PLEC) conferred increased ESCC risk (Adjusted OR = 2.085, 95% CI = 1.493-2.912, P < 0.001 for UGT2B28. Adjusted OR = 3.725, 95% CI = 1.026-13.533, P = 0.046 for PLEC). mRNA level was lower in UGT2B28 loss genotyped esophageal tissues than in two-copy tissues, indicating that UGT2B28 loss genotypes modify ESCC susceptibility perhaps by decreasing UGT2B28 expression level and enzyme activity. In addition, an association was drawn between germline copy number variations and somatic alterations for PLEC, UGT2B17 and UGT2B28, but not for other candidate loci.

Objective To identify methylation quantitative trait loci (mQTLs) correlating with osteoarthritis (OA) risk alleles and to undertake mechanistic characterization as a means of target gene prioritization. Methods We used genome-wide genotyping and cartilage DNA methylation array data in a discovery screen of novel OA risk loci. This was followed by methylation, gene expression analysis, and genotyping studies in additional cartilage samples, accompanied by in silico analyses. Results We identified 4 novel OA mQTLs. The most significant mQTL contained 9 CpG sites where methylation correlated with OA risk genotype, with 5 of the CpG sites having P values PLEC gene and form 2 distinct clusters. We were able to prioritize PLEC and the adjacent gene GRINA as independent targets of the OA risk. We identified PLEC and GRINA expression QTLs operating in cartilage, as well as methylation-expression QTLs operating on the 2 genes. GRINA and PLEC also demonstrated differential expression between OA hip and non-OA hip cartilage. Conclusion PLEC encodes plectin, a cytoskeletal protein that maintains tissue integrity by regulating intracellular signaling in response to mechanical stimuli. GRINA encodes the ionotropic glutamate receptor TMBIM3 (transmembrane BAX inhibitor 1 motif-containing protein family member 3), which regulates cell survival. Based on our results, we hypothesize that in a joint predisposed to OA, expression of these genes alters in order to combat aberrant biomechanics, and that this is epigenetically regulated. However, carriage of the OA risk-conferring allele at this locus hinders this response and contributes to disease development.