setd2

SET-domain containing 2 (SETD2) is a histone methyltransferase and an epigenetic modifier with oncogenic functionality. In the current study, we investigated the potential prognostic role of SETD2 in prostate cancer. A cohort of 202 patients' samples was assembled on tissue microarrays (TMAs) containing incidental, advanced, and castrate-resistant CRPCa cases. Our data showed significant elevated SETD2 expression in advanced and castrate-resistant disease (CRPCa) compared to incidental cases (2.53 ± 0...

UNLABELLED: Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, particularly in women. EGFR mutations and anaplastic lymphoma kinase (ALK) fusions are major genetic alterations observed in NSLA, and NSLA with these alterations have been well studied and can be treated with targeted therapies. To provide insights into the molecular profile of NSLA without EGFR and ALK alterations (NENA), we selected 141 NSLA tissues and performed proteogenomic characterization, including whole genome sequencing (WGS), transcriptomic, methylation EPIC array, total proteomic, and phosphoproteomic analyses...

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease characterized by the breakdown of joint cartilage and underlying bone. Macrophages are a type of white blood cell that plays a critical role in the immune system and can be found in various tissues, including joints. Research on the relationship between OA and macrophages is essential to understand the mechanisms underlying the development and progression of OA. OBJECTIVE: This study was performed to analyze the functions of the IRF1-GCN5-SETD2-SMARCC1 axis in osteoarthritis (OA) development...

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor...

BACKGROUND: Megakaryocytes (MKs) are polyploid cells responsible for producing ∼1011 platelets daily in humans. Unraveling the mechanisms regulating megakaryopoiesis holds the promise for the production of clinical-grade platelets from stem cells, overcoming significant current limitations in platelet transfusion medicine. Previous work identified that loss of the epigenetic regulator SETD2 was associated with an increased platelet count in mice. However, the role of SETD2 in megakaryopoiesis remains unknown...

BACKGROUND: Small intestinal monomorphic-epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma originating in the gastrointestinal tract. This study aimed to investigate the clinicopathological features, immunophenotypes, and molecular genetic changes of MEITL. METHODS: The clinicopathological data for three patients with surgically resected MEITL of the small intestine were collected. Next, immunohistochemical labeling, Epstein-Barr virus (EBV) in situ hybridization, assessment of clonal rearrangement of T-cell receptor (TCR) genes, and next-generation sequencing (NGS) were performed...

BACKGROUND: As one of the most common tumors, the pathogenesis and progression of clear cell renal cell carcinoma (ccRCC) in the immune microenvironment are still unknown. METHODS: The differentially expressed immune-related lncRNA (DEirlncRNA) was screened through co-expression analysis and the limma package of R, which based on the ccRCC project of the TCGA database. Then, we designed the risk model by irlncRNA pairs. In RCC patients, we have compared the area under the curve, calculated the Akaike Information Criterion (AIC) value of the 5-year receiver operating characteristic curve, determined the cut-off point, and established the optimal model for distinguishing the high-risk group from the low-risk group...

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare and aggressive T-cell neoplasm associated with poor survival. We report a case of MEITL that presented as an ulcerated mass in the jejunum with perforation. Microscopic examination showed that the neoplasm involved the full thickness of the intestinal wall, extended into the mesentery, and was composed of monomorphic, small to medium-size cells. Immunohistochemical analysis showed that the neoplastic cells were positive for T-cell receptor (TCR) delta, CD3, CD7, CD8 (small subset), BCL-2 and TIA-1, and negative for TCR beta, CD4, CD5, CD10, CD20, CD30, CD34, CD56, CD57, CD99, ALK, cyclin D1, granzyme B, MUM1/IRF4, and TdT...

INTRODUCTION: T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease with poor prognosis and inferior outcome. Although multiple studies have been perform on genomics of T-ALL, data from Indian sub-continent is scarce. METHODS: In the current study we aimed to identify the genetic variability of T-ALL in an Indian cohort of pediatric (age ≤ 12 years) T-ALL patients (n = 25) by whole transcriptome sequencing along with whole exome sequencing and correlated the findings with clinical characteristics and disease outcome...

Protein lysine methyltransferases (PKMTs) transfer up to three methyl groups to the side chains of lysine residues in proteins and fulfill important regulatory functions by controlling protein stability, localization and protein/protein interactions. The methylation reactions are highly regulated, and aberrant methylation of proteins is associated with several types of diseases including neurologic disorders, cardiovascular diseases, and various types of cancer. This review describes novel insights into the catalytic machinery of various PKMTs achieved by the combined application of biochemical experiments and simulation approaches during the last years, focusing on clinically relevant and well-studied enzymes of this group like DOT1L, SMYD1-3, SET7/9, G9a/GLP, SETD2, SUV420H2, NSD1/2, different MLLs and EZH2...

Proper formation of the hippocampus is crucial for the brain to execute memory and learning functions. However, many questions remain regarding how pyramidal neurons (PNs) of the hippocampus mature and precisely position. Here we revealed that Setd2 , the methyltransferase for histone 3 lysine 36 trimethylation (H3K36me3), is essential for the precise localization and maturation of PNs in the hippocampal CA1. The ablation of Setd2 in neural progenitors leads to irregular lamination of the CA1 and increased numbers of PNs in the stratum oriens...

Neoadjuvant chemotherapy (NACT) is a therapeutic option for locally advanced cervical cancer (LACC) patients. This study was aimed to identify potential liquid biopsy biomarkers to monitor the NACT response. Through targeted next-generation sequencing (NGS) analysis of circulating tumor DNA (ctDNA) and tumor tissue DNA (ttDNA) taken from LACC patients undergoing platinum-based NACT, 64 genes with mutations emerge during NACT in the non-responders but none in the responders. Among them, the PBRM1, SETD2, and ROS1 mutations were frequently detected in the ctDNA and ttDNA of the non-responders, and mutant PBRM1 was associated with poorer survival of patients...

A better understanding of ABL1-kinase domain mutation-independent causes of tyrosine kinase inhibitor (TKI) resistance is needed for BCR::ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). While TKIs have dramatically improved outcomes, a subset of patients still experiences relapsed or refractory disease. We aimed to identify potential biomarkers for intrinsic TKI resistance at diagnosis in 32 pediatric and 19 adult BCR::ABL1-positive BCP-ALL samples. Reduced ex vivo imatinib sensitivity was observed in cells derived from newly diagnosed patients who relapsed after combined TKI and chemotherapy treatment compared with cells derived from patients who remained in continuous complete remission...

PURPOSE: Cabozantinib (CAB) as monotherapy or in combination with immune checkpoint inhibitors is used for systemic treatment of metastatic renal cell carcinoma (mRCC). However, little is known about predictors of treatment response to CAB. For this reason, known genomic drivers were examined to identify potential predictors of treatment response with CAB. METHODS: Twenty mRCC patients receiving monotherapy (≥ first-line) with CAB were prospectively included...

Histone modifications maintain genomic stability and orchestrate gene expression at the chromatin level. Benzo [a]pyrene (BaP) is the ubiquitous carcinogen widely spread in the environment, but the role and regulatory mechanism of histone modification in its toxic effects remain largely undefined. In this study, we found a dose-dependent reduction of histone H3 methylations at lysine4, lysine9, lysine27, lysine36 in HBE cells treated with BaP. We observed that inhibiting H3K27 and H3K36 methylation impaired cell proliferation, whereas the loss of H3K4, H3K9, H3K27, and H3K36 methylation led to increased genomic instability and delayed DNA repair...

Arcagen (NCT02834884) is a European prospective study aiming at defining the molecular landscape of rare cancers for treatment guidance. We present data from the cohort of rare thoracic tumors. Patients with advanced pleural mesothelioma (PM) or thymic epithelial tumors (TET) underwent genomic profiling with large targeted assay [>300 genes, tumor mutational burden (TMB), microsatellite instability (MSI) status] on formalin-fixed paraffin-embedded (FFPE) or plasma samples. EORTC molecular tumor board (MTB) advised for biomarker-guided treatments...

Coordinated metabolic reprogramming and epigenetic remodeling are critical for modulating T cell function and differentiation. However, how the epigenetic modification controls Th17/Treg cell balance via metabolic reprogramming remains obscure. Here, we find that Setd2, a histone H3K36 trimethyltransferase, suppresses Th17 development but promotes iTreg cell polarization via phospholipid remodeling. Mechanistically, Setd2 up-regulates transcriptional expression of lysophosphatidylcholine acyltransferase 4 (Lpcat4) via directly catalyzing H3K36me3 of Lpcat4 gene promoter in T cells...

Mutations in SETD2 are among the most prevalent drivers of renal cell carcinoma (RCC). We identified a novel single nucleotide polymorphism (SNP) in SETD2, E902Q, within a subset of RCC patients, which manifests as both an inherited or tumor-associated somatic mutation. To determine if the SNP is biologically functional, we used CRISPR-based genome editing to generate the orthologous mutation within the Drosophila melanogaster Set2 gene. In Drosophila, the homologous amino acid substitution, E741Q, reduces H3K36me3 levels comparable to Set2 knockdown, and this loss is rescued by reintroduction of a wild-type Set2 transgene...

BACKGROUND: Identifying biomarkers for metastatic renal cell carcinoma (mRCC) is an unmet need in actual immunotherapy era. Available data regarding chromosome 3p genes (i.e., VHL, PBRM1, SETD2) mutations as potential predictors for therapy response is conflicting. We describe the impact of these mutations on clinical outcomes in mRCC patients treated with immune checkpoint inhibitor (ICI)-doublet or ICI/tyrosine kinase inhibitor (TKI) combinations. METHODS: We performed a single-center retrospective analysis on mRCC patients treated with first line ICI/ICI or ICI/TKI...

BACKGROUND: Kidney renal clear cell cancer (KIRC) is a type of urological cancer that occurs worldwide. Core fucosylation (CF), as the most common post-translational modification, is involved in the tumorigenesis. METHODS: The alterations of CF-related genes were summarized in pan-cancer. The "ConsensusClusterPlus" package was utilized to identify two CF-related KIRC subtypes. The "ssgsea" function was chosen to estimate the CF score, signaling pathways and cell deaths...