Gene Summary

Gene:NR3C2; nuclear receptor subfamily 3 group C member 2
Aliases: MR, MCR, MLR, NR3C2VIT
Summary:This gene encodes the mineralocorticoid receptor, which mediates aldosterone actions on salt and water balance within restricted target cells. The protein functions as a ligand-dependent transcription factor that binds to mineralocorticoid response elements in order to transactivate target genes. Mutations in this gene cause autosomal dominant pseudohypoaldosteronism type I, a disorder characterized by urinary salt wasting. Defects in this gene are also associated with early onset hypertension with severe exacerbation in pregnancy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:mineralocorticoid receptor
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: NR3C2 (cancer-related)

Liu Z, Liu H, Liu Z, Zhang J
Oligodendroglial tumours: subventricular zone involvement and seizure history are associated with CIC mutation status.
BMC Neurol. 2019; 19(1):134 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: CIC-mutant oligodendroglial tumours linked to better prognosis. We aim to investigate associations between CIC gene mutation status, MR characteristics and clinical features.
METHODS: Imaging and genomic data from the Cancer Genome Atlas and the Cancer Imaging Archive (TCGA/TCIA) for 59 patients with oligodendroglial tumours were used. Differences between CIC mutation and CIC wild-type were tested using Chi-square test and binary logistic regression analysis.
RESULTS: In univariate analysis, the clinical variables and MR features, which consisted 3 selected features (subventricular zone[SVZ] involvement, volume and seizure history) were associated with CIC mutation status (all p < 0.05). A multivariate logistic regression analysis identified that seizure history (no vs. yes odd ratio [OR]: 28.960, 95 confidence interval [CI]:2.625-319.49, p = 0.006) and SVZ involvement (SVZ- vs. SVZ+ OR: 77.092, p = 0.003; 95% CI: 4.578-1298.334) were associated with a higher incidence of CIC mutation status. The nomogram showed good discrimination, with a C-index of 0.906 (95% CI: 0.812-1.000) and was well calibrated. SVZ- group has increased (SVZ- vs. SVZ+, hazard ratio [HR]: 4.500, p = 0.04; 95% CI: 1.069-18.945) overall survival.
CONCLUSIONS: Absence of seizure history and SVZ involvement (-) was associated with a higher incidence of CIC mutation.

Augelli R, Ciceri E, Ghimenton C, et al.
Magnetic resonance diffusion-tensor imaging metrics in High Grade Gliomas: Correlation with IDH1 gene status in WHO 2016 era.
Eur J Radiol. 2019; 116:174-179 [PubMed] Related Publications
PURPOSE: To evaluate any possible correlation between the presence of Isocitrate DeHydrogenase 1 mutation (IDH1m) and specific DTI (Diffusion Tensor Imaging) metrics, such as Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD) and Axial Diffusivity (AD).
METHODS: We retrospectively analyzed 47 patients who underwent an advanced-MR study with DTI followed by surgical intervention with a subsequent histologic diagnosis of High-Grade Glioma (HGG) and immunohistochemical evaluation of IDH1 (Isocitrate DeHydrogenase) mutation status. For each DTI metrics we measured the ratio between tumor and normal tissue and we evaluated the correlation with IDH1 mutation.
RESULTS: We observed a positive correlation with IDH1 status and RD and MD data. No correlation was demonstrated between IDH1 status and FA and AD.
DISCUSSION: Our results support the hypothesis that the number of residual axonal fibers, extracellular matrix composition and the presence of colliquated tissue, may together contribute to a global RD increase in HGG, with a relatively higher increase in IDH1m tumors.
CONCLUSIONS: Our data are in favor of a need for multimodal advance evaluation of HGG. DTI metrics help to analyze IDH1 mutation status, in order to better characterize the lesions and to tailor treatment and follow up.

Zhang Q, Lu Y, Xu X, et al.
MR molecular imaging of HCC employing a regulated ferritin gene carried by a modified polycation vector.
Int J Nanomedicine. 2019; 14:3189-3201 [PubMed] Free Access to Full Article Related Publications

Benstead-Hume G, Chen X, Hopkins SR, et al.
Predicting synthetic lethal interactions using conserved patterns in protein interaction networks.
PLoS Comput Biol. 2019; 15(4):e1006888 [PubMed] Free Access to Full Article Related Publications
In response to a need for improved treatments, a number of promising novel targeted cancer therapies are being developed that exploit human synthetic lethal interactions. This is facilitating personalised medicine strategies in cancers where specific tumour suppressors have become inactivated. Mainly due to the constraints of the experimental procedures, relatively few human synthetic lethal interactions have been identified. Here we describe SLant (Synthetic Lethal analysis via Network topology), a computational systems approach to predicting human synthetic lethal interactions that works by identifying and exploiting conserved patterns in protein interaction network topology both within and across species. SLant out-performs previous attempts to classify human SSL interactions and experimental validation of the models predictions suggests it may provide useful guidance for future SSL screenings and ultimately aid targeted cancer therapy development.

Knebel C, Neumann J, Schwaiger BJ, et al.
Differentiating atypical lipomatous tumors from lipomas with magnetic resonance imaging: a comparison with MDM2 gene amplification status.
BMC Cancer. 2019; 19(1):309 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To evaluate the diagnostic value of MR imaging for the differentiation of lipomas and atypical lipomatous tumors (ALT) in comparison with histology and MDM2 amplification status.
METHODS: Patients with well-differentiated lipomatous tumors (n = 113), of which 66 were diagnosed as lipoma (mean age 53 years (range, 13-82); 47% women) and 47 as atypical lipomatous tumor (ALT; mean age 60 years (range, 28-88); 64% women), were included into this study using histology and MDM2 amplification status by fluorescence in situ hybridization (FISH) as standard of reference. Preoperative MR images were retrospectively assessed by two radiologists for the following imaging features: maximum tumor diameter (mm) as well as the affected compartment (intramuscular, intermuscular or subcutaneous), septa (absent, thin (< 2 mm) or thick septa (> 2 mm) with nodular components); contrast enhancing areas within the lipomatous tumor (< 1/3 of the tumor volume, > 1/3 of the tumor volume); RESULTS: Of the 47 patients with ALT, 40 (85.1%) presented thick septa (> 2 mm) and this finding significantly increased the likelihood of ALT (OR 6.24, 95% CI 3.36-11.59; P < 0.001). The likelihood of ALT was increased if the tumor exceeded a maximum diameter of 130.0 mm (OR 2.74, 95% CI 1.82-4.11, P < 0.001). The presence of contrast enhancement in lipomatous tumors significantly increased the likelihood of ALT (Odds ratio (OR) 2.95, 95% confidence interval (CI) 2.01-4.31; P < 0.001). Of the lipomas, 21.1% were located subcutaneously, 63.6% intramuscularly and 15.2% intermuscularly. On the other hand, none of the ALTs were located subcutaneously, the majority was located intermuscularly (87.3%) and a small number of ALTs was located intramuscularly (12.7%).
CONCLUSIONS: Our results suggest that using specific morphological MR imaging characteristics (maximum tumor diameter, thick septa and contrast enhancement) and the information on the localization of the lipomatous tumor, a high sensitivity and substantial specificity can be achieved for the diagnosis of lipomas and ALTs.

Cowman S, Fan YN, Pizer B, Sée V
Decrease of Nibrin expression in chronic hypoxia is associated with hypoxia-induced chemoresistance in some brain tumour cells.
BMC Cancer. 2019; 19(1):300 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Solid tumours are less oxygenated than normal tissues. This is called tumour hypoxia and leads to resistance to radiotherapy and chemotherapy. The molecular mechanisms underlying such resistance have been investigated in a range of tumour types, including the adult brain tumours glioblastoma, yet little is known for paediatric brain tumours. Medulloblastoma (MB) is the most common malignant brain tumour in children. We aimed to elucidate the impact of hypoxia on the sensitivity of MB cells to chemo- and radiotherapy.
METHODS: We used two MB cell line (D283-MED and MEB-Med8A) and a widely used glioblastoma cell line (U87MG) for comparison. We applied a range of molecular and cellular techniques to measure cell survival, cell cycle progression, protein expression and DNA damage combined with a transcriptomic micro-array approach in D283-MED cells, for global gene expression analysis in acute and chronic hypoxic conditions.
RESULTS: In D283-MED and U87MG, chronic hypoxia (5 days), but not acute hypoxia (24 h) induced resistance to chemotherapy and X-ray irradiation. This acquired resistance upon chronic hypoxia was present but less pronounced in MEB-Med8A cells. Using transcriptomic analysis in D283-MED cells, we found a large transcriptional remodelling upon long term hypoxia, in particular the expression of a number of genes involved in detection and repair of double strand breaks (DSB) was altered. The levels of Nibrin (NBN) and MRE11, members of the MRN complex (MRE11/Rad50/NBN) responsible for DSB recognition, were significantly down-regulated. This was associated with a reduction of Ataxia Telangiectasia Mutated (ATM) activation by etoposide, indicating a profound dampening of the DNA damage signalling in hypoxic conditions. As a consequence, p53 activation by etoposide was reduced, and cell survival enhanced. Whilst U87MG shared the same dampened p53 activity, upon chemotherapeutic drug treatment in chronic hypoxic conditions, these cells used a different mechanism, independent of the DNA damage pathway.
CONCLUSION: Together our results demonstrate a new mechanism explaining hypoxia-induced resistance involving the alteration of the response to DSB in D283-MED cells, but also highlight the cell type to cell type diversity and the necessity to take into account the differing tumour genetic make-up when considering re-sensitisation therapeutic protocols.

Lawrenson K, Song F, Hazelett DJ, et al.
Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.
Gynecol Oncol. 2019; 153(2):343-355 [PubMed] Related Publications
OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.
METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.
RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10
CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

Liu L, Zhang S, Liu X, Liu J
Aberrant promoter 2 methylation‑mediated downregulation of protein tyrosine phosphatase, non‑receptor type 6, is associated with progression of esophageal squamous cell carcinoma.
Mol Med Rep. 2019; 19(4):3273-3282 [PubMed] Related Publications
The human protein tyrosine phosphatase, non‑receptor type 6 (PTPN6) gene is located on chromosome 12p13 and encodes an Mr 68,000 non‑receptor type protein‑tyrosine phosphatase. The PTPN6 gene has been considered as a candidate tumor suppressor in hematological and solid malignancies, and promoter methylation may be an epigenetic modification silencing its expression. However, the detailed role of PTPN6 and its promoter methylation status in the pathogenesis of esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. The aim of the present study was to investigate PTPN6 expression in ESCC tissues and esophageal cancer cell lines, detect the effect of CpG hypermethylation on the activity of PTPN6, and additionally elucidate the role and prognostic significance of PTPN6 in ESCC tumorigenesis and progression. The expression of PTPN6 was identified to be significantly downregulated in esophageal cancer cell lines and ESCC tissues. Marked upregulation of PTPN6 was detected in 5‑aza‑2'‑deoxycytidine‑treated esophageal cancer cells, and frequent hypermethylation of the CpG sites within the P2 promoter (P2) was detected in ESCC tissues and esophageal cancer cell lines. The expression and methylation status of PTPN6 was associated with tumor node metastasis stage, pathological differentiation and lymph node metastasis in patients with ESCC. Aberrant hypermethylation of the P2 exhibited marked tumor specificity and was identified to be associated with the expression level of PTPN6. Downregulation and hypermethylation of PTPN6 were identified to be associated with poor ESCC patient survival. Furthermore, upregulation of PTPN6 inhibited the proliferation and invasion of esophageal cancer cells in vitro. The results of the present study suggest that PTPN6 may serve as a tumor suppressor in ESCC, and it may serve as a potential target for antitumor therapy.

Chen W, Shen B, Sun X
Analysis of Progress and Challenges of EGFR-Targeted Molecular Imaging in Cancer With a Focus on Affibody Molecules.
Mol Imaging. 2019 Jan-Dec; 18:1536012118823473 [PubMed] Free Access to Full Article Related Publications
Epidermal growth factor receptor (EGFR)-targeted cancer therapy requires an accurate estimation of EGFR expression in tumors to identify responsive patients, monitor therapeutic effect, and estimate prognosis. The EGFR molecular imaging is an optimal method for evaluating EGFR expression in vivo accurately and noninvasively. In this review, we discuss the recent advances in EGFR-targeted molecular imaging in cancer, with a special focus on the development of imaging agents, including epidermal growth factor (EGF) ligand, monoclonal antibodies, antibody fragments, Affibody, and small molecules. Each substrate or probe, whether it is an endogenous ligand, antibody, peptide, or small molecule labeled with fluorochrome or radionuclide, has unique advantages and limitations. Antibody-based probes have high affinity but a long metabolic cycle and therefore offer poor imaging quality. Affibody molecules promise to surpass antibody-based probes due to their small size, stable chemical properties, and high affinity to the target. Small-molecule probes are safe, have favorable pharmacokinetics, and show high affinity and specificity, in addition to having an ideal size, but are inadequate for delayed imaging after injection due to their fast clearance.

Garcia-Moreno M, Noerenberg M, Ni S, et al.
System-wide Profiling of RNA-Binding Proteins Uncovers Key Regulators of Virus Infection.
Mol Cell. 2019; 74(1):196-211.e11 [PubMed] Free Access to Full Article Related Publications
The compendium of RNA-binding proteins (RBPs) has been greatly expanded by the development of RNA-interactome capture (RIC). However, it remained unknown if the complement of RBPs changes in response to environmental perturbations and whether these rearrangements are important. To answer these questions, we developed "comparative RIC" and applied it to cells challenged with an RNA virus called sindbis (SINV). Over 200 RBPs display differential interaction with RNA upon SINV infection. These alterations are mainly driven by the loss of cellular mRNAs and the emergence of viral RNA. RBPs stimulated by the infection redistribute to viral replication factories and regulate the capacity of the virus to infect. For example, ablation of XRN1 causes cells to be refractory to SINV, while GEMIN5 moonlights as a regulator of SINV gene expression. In summary, RNA availability controls RBP localization and function in SINV-infected cells.

Legge DN, Shephard AP, Collard TJ, et al.
BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells.
Dis Model Mech. 2019; 12(3) [PubMed] Free Access to Full Article Related Publications
To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently, B-cell lymphoma 3 (BCL-3; a key regulator of NF-κB signalling) has been recognised as an important oncogenic player in solid tumours. Although reported to be overexpressed in a subset of colorectal cancers (CRCs), the role of BCL-3 expression in colorectal tumorigenesis remains poorly understood. Despite evidence in the literature that BCL-3 may interact with β-catenin, it is perhaps surprising, given the importance of deregulated Wnt/β-catenin/T-cell factor (TCF) signalling in colorectal carcinogenesis, that the functional significance of this interaction is not known. Here, we show for the first time that BCL-3 acts as a co-activator of β-catenin/TCF-mediated transcriptional activity in CRC cell lines and that this interaction is important for Wnt-regulated intestinal stem cell gene expression. We demonstrate that targeting BCL-3 expression (using RNA interference) reduced β-catenin/TCF-dependent transcription and the expression of intestinal stem cell genes

Poźniak J, Nsengimana J, Laye JP, et al.
Genetic and Environmental Determinants of Immune Response to Cutaneous Melanoma.
Cancer Res. 2019; 79(10):2684-2696 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
The immune response to melanoma improves the survival in untreated patients and predicts the response to immune checkpoint blockade. Here, we report genetic and environmental predictors of the immune response in a large primary cutaneous melanoma cohort. Bioinformatic analysis of 703 tumor transcriptomes was used to infer immune cell infiltration and to categorize tumors into immune subgroups, which were then investigated for association with biological pathways, clinicopathologic factors, and copy number alterations. Three subgroups, with "low", "intermediate", and "high" immune signals, were identified in primary tumors and replicated in metastatic tumors. Genes in the low subgroup were enriched for cell-cycle and metabolic pathways, whereas genes in the high subgroup were enriched for IFN and NF-κB signaling. We identified high MYC expression partially driven by amplification, HLA-B downregulation, and deletion of IFNγ and NF-κB pathway genes as the regulators of immune suppression. Furthermore, we showed that cigarette smoking, a globally detrimental environmental factor, modulates immunity, reducing the survival primarily in patients with a strong immune response. Together, these analyses identify a set of factors that can be easily assessed that may serve as predictors of response to immunotherapy in patients with melanoma. SIGNIFICANCE: These findings identify novel genetic and environmental modulators of the immune response against primary cutaneous melanoma and predict their impact on patient survival.

Latysheva A, Emblem KE, Brandal P, et al.
Dynamic susceptibility contrast and diffusion MR imaging identify oligodendroglioma as defined by the 2016 WHO classification for brain tumors: histogram analysis approach.
Neuroradiology. 2019; 61(5):545-555 [PubMed] Related Publications
PURPOSE: According to the revised World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) of 2016, oligodendrogliomas are now defined primarily by a specific molecular signature (presence of IDH mutation and 1p19q codeletion). The purpose of our study was to assess the value of dynamic susceptibility contrast MR imaging (DSC-MRI) and diffusion-weighted imaging (DWI) to characterize oligodendrogliomas and to distinguish them from astrocytomas.
METHODS: Seventy-one adult patients with untreated WHO grade II and grade III diffuse infiltrating gliomas and known 1p/19q codeletion status were retrospectively identified and analyzed using relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) maps based on whole-tumor volume histograms. The Mann-Whitney U test and logistic regression were used to assess the ability of rCBV and ADC to differentiate between oligodendrogliomas and astrocytomas both independently, but also related to the WHO grade. Prediction performance was evaluated in leave-one-out cross-validation (LOOCV).
RESULTS: Oligodendrogliomas showed significantly higher microvascularity (higher rCBV
CONCLUSION: Histogram-derived rCBV and ADC parameter may be used as biomarkers for identification of oligodendrogliomas and may help characterize diffuse gliomas based upon their genetic characteristics.

Chan ASL, Narita M
Short-term gain, long-term pain: the senescence life cycle and cancer.
Genes Dev. 2019; 33(3-4):127-143 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
Originally thought of as a stress response end point, the view of cellular senescence has since evolved into one encompassing a wide range of physiological and pathological functions, including both protumorignic and antitumorigenic features. It has also become evident that senescence is a highly dynamic and heterogenous process. Efforts to reconcile the beneficial and detrimental features of senescence suggest that physiological functions require the transient presence of senescent cells in the tissue microenvironment. Here, we propose the concept of a physiological "senescence life cycle," which has pathological consequences if not executed in its entirety.

Asiri A, Raposo TP, Alfahed A, Ilyas M
TGFβ1-induced cell motility but not cell proliferation is mediated through Cten in colorectal cancer.
Int J Exp Pathol. 2018; 99(6):323-330 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Cten (C-terminal tensin-like) is a member of the tensin protein family found in complex with integrins at focal adhesions. It promotes epithelial-mesenchymal transition (EMT) and cell motility. The precise mechanisms regulating Cten are unknown, although we and others have shown that Cten could be under the regulation of several cytokines and growth factors. Since transforming growth factor beta 1 (TGF-β1) regulates integrin function and promotes EMT/cell motility, we were prompted to investigate whether TGF-β1 induces EMT and cell motility through Cten signalling in colorectal cancer. TGF-β1 signalling was modulated by either stimulation with TGF-β1 or knockdown of TGF-β1 in the CRC cell lines SW620 and HCT116. The effect of this modulation on expression of Cten, EMT markers and on cellular function was tested. The role of Cten as a direct mediator of TGF-β1 signalling was investigated in a CRC cell line in which the Cten gene had been deleted (SW620

Farawela HM, Zawam HM, Al-Wakeel HA, et al.
Expression pattern and prognostic implication of SALL4 gene in myeloid leukemias: a case-control study.
Scand J Clin Lab Invest. 2019 Feb - Apr; 79(1-2):65-70 [PubMed] Related Publications
SALL4 is a transcription factor that retains stem cells in an undifferentiated state and promotes its self-renewal. In addition, it is implicated in leukemogenesis via its effect on leukemic stem cells. This study aimed to characterize the expression pattern of SALL4 gene in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) at different progression phases of the leukemic process and to assess its prognostic significance. Real-time PCR was used in 106 patients: 54 AML patients; 43 de novo and 11 in complete remission (CR), 52 CML patients; 31 in chronic phase (CP), 11 in deep molecular response (MR

Hou Y, Zhang Y, Qin L, et al.
Interferon-induced transmembrane protein-3 rs12252-CC is associated with low differentiation and progression of hepatocellular carcinoma.
Medicine (Baltimore). 2019; 98(2):e13996 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Interferon-induced transmembrane protein 3 (IFITM3) is a component of ISG (Interferon-Stimulated Gene) family. The association between IFITM3 and hepatocellular carcinoma (HCC) has been reported. While the relationship between this genetic variation and the progress of HCC remains unclear. To address this issue, we explore the relationship between the IFITM3-rs12252 genetic variants and the progression of HCC in this study.A total of 336 candidates were enrolled in the study, including 156 patients with HBV related HCC and 180 patients with chronic Hepatitis B infections or liver cirrhosis. Liver cirrhosis or chronic hepatitis B were diagnosed with clinical characteristics and staging, laboratory testing, and imaging results of viral infection and hepatic damage. Polymerase chain reaction (PCR) was employed to determine the gene polymorphism of IFITM3, and analyzed with the GraphPad Prism v 5.The patients with HCC had a significantly higher proportion of IFITM3 rs12252-CC as compared with the patients with chronic HBV infection or liver cirrhosis. Moreover, the distribution of CC genotype in HCC patients with low differentiation was significantly higher than that in those with high differentiation. Furthermore, the patients with CC genotype were found with bigger tumor size, higher percentage of vascular thrombosis, higher distribution of low differentiation and higher 5-year relapse rate than those with CT/TT genotypes.This study indicates a correlation between the IFITM3-rs12252 CC genotype and the progression of HCC.

Ng JCF, Quist J, Grigoriadis A, et al.
Pan-cancer transcriptomic analysis dissects immune and proliferative functions of APOBEC3 cytidine deaminases.
Nucleic Acids Res. 2019; 47(3):1178-1194 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
APOBEC3 cytidine deaminases are largely known for their innate immune protection from viral infections. Recently, members of the family have been associated with a distinct mutational activity in some cancer types. We report a pan-tissue, pan-cancer analysis of RNA-seq data specific to the APOBEC3 genes in 8,951 tumours, 786 cancer cell lines and 6,119 normal tissues. By deconvolution of levels of different cell types in tumour admixtures, we demonstrate that APOBEC3B (A3B), the primary candidate as a cancer mutagen, shows little association with immune cell types compared to its paralogues. We present a pipeline called RESPECTEx (REconstituting SPecific Cell-Type Expression) and use it to deconvolute cell-type specific expression levels in a given cohort of tumour samples. We functionally annotate APOBEC3 co-expressing genes, and create an interactive visualization tool which 'barcodes' the functional enrichment ( These analyses reveal that A3B expression correlates with cell cycle and DNA repair genes, whereas the other APOBEC3 members display specificity for immune processes and immune cell populations. We offer molecular insights into the functions of individual APOBEC3 proteins in antiviral and proliferative contexts, and demonstrate the diversification this family of enzymes displays at the transcriptomic level, despite their high similarity in protein sequences and structures.

Went M, Sud A, Speedy H, et al.
Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.
Blood Cancer J. 2018; 9(1):1 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R

Kim E, Mema E, Axelrod D, et al.
Preliminary analysis: Background parenchymal 18F-FDG uptake in breast cancer patients appears to correlate with background parenchymal enhancement and to vary by distance from the index cancer.
Eur J Radiol. 2019; 110:163-168 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
PURPOSE: To investigate how breast parenchymal uptake (BPU) of 18F-FDG on positron emission tomography/ magnetic resonance imaging (PET/MRI) in patients with breast cancer is related to background parenchymal enhancement (BPE), amount of fibroglandular tissue (FGT), and age, as well as whether BPU varies as a function of distance from the primary breast cancer.
MATERIALS AND METHODS: In this institutional review board (IRB)-approved retrospective study, 40 patients (all female, ages 32-80 years, mean 52 years) gave informed consent prior to undergoing contrast enhanced breast PET/MRI from 3/2015 to 2/2018. Of the 40 patients, 6 were excluded for multicentric or bilateral cancers, 1 for current lactation and 6 because the raw data from their scans were corrupted. The remaining 27 patients (all female, ages 33 to 80 years, mean age 53 years) comprised the study population. Prone PET and contrast-enhanced MR data were acquired simultaneously on a 3-T integrated PET/ MR system. BPU was measured as SUVmax of a 1.5 cm
RESULTS: BPU was significantly greater in the same quadrant as the breast cancer as compared with the opposite quadrant of the same breast (p < 0.001 for both readers) and was significantly greater in the opposite quadrant of the same breast compared to the matched quadrant of the contralateral breast (p = 0.002 for reader 1 and <0.001 for reader 2). While the FGT SUVmax in the same quadrant as the cancer correlated significantly with SUVmax of the index lesion, the FGT SUVmax in the opposite quadrant of the same breast and in the matched quadrant of the contralateral breast did not. The FGT SUVmax in the contralateral breast positively correlated with the degree of BPE and negatively correlated with age, but did not show a significant correlation with the amount of FGT for either reader.
CONCLUSION: There appears to be an inverse correlation between metabolic activity of normal breast parenchyma and distance from the index cancer. BPU significantly correlates with BPE.

Cline MS, Liao RG, Parsons MT, et al.
BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2.
PLoS Genet. 2018; 14(12):e1007752 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

Tzelepis K, De Braekeleer E, Aspris D, et al.
SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4.
Nat Commun. 2018; 9(1):5378 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4 and MED24. We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML.

Meisenberg C, Pinder SI, Hopkins SR, et al.
Repression of Transcription at DNA Breaks Requires Cohesin throughout Interphase and Prevents Genome Instability.
Mol Cell. 2019; 73(2):212-223.e7 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Cohesin subunits are frequently mutated in cancer, but how they function as tumor suppressors is unknown. Cohesin mediates sister chromatid cohesion, but this is not always perturbed in cancer cells. Here, we identify a previously unknown role for cohesin. We find that cohesin is required to repress transcription at DNA double-strand breaks (DSBs). Notably, cohesin represses transcription at DSBs throughout interphase, indicating that this is distinct from its known role in mediating DNA repair through sister chromatid cohesion. We identified a cancer-associated SA2 mutation that supports sister chromatid cohesion but is unable to repress transcription at DSBs. We further show that failure to repress transcription at DSBs leads to large-scale genome rearrangements. Cancer samples lacking SA2 display mutational patterns consistent with loss of this pathway. These findings uncover a new function for cohesin that provides insights into its frequent loss in cancer.

Vervoort SJ, de Jong OG, Roukens MG, et al.
Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis.
Elife. 2018; 7 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
The expression of the transcription factor

Alifu M, Hu YH, Dong T, Wang RZ
HLA-A*30:01 and HLA-A*33:03 are the protective alleles while HLA-A*01:01 serves as the susceptible gene for cervical cancer patients in Xinjiang, China.
J Cancer Res Ther. 2018 Oct-Dec; 14(6):1266-1272 [PubMed] Related Publications
Objective: This study aims to investigate the distribution of HLA-A genes and identify alleles related to cervical cancer.
Materials and Methods: A total of 252 cervical cancer patients (56 Han ethnic and 196 Uyghur ethnic) and 213 controls (103 Han ethnic and 110 Uyghur ethnic) were recruited in this study. HLA-A alleles were examined by polymerase chain reaction with sequence-specific primers. The frequencies of different HLA-A alleles were compared between the two ethnic groups as well as patients and controls. The correlation of HLA-A frequencies with various clinical characteristics and short-term treatment efficacy was analyzed.
Results: (1) Significantly higher frequencies of HLA-A*03:01 and HLA-A*03:02 and lower frequencies of HLA-A*11:01, HLA-A*24:02, and HLA-A*30:01 were observed in the Uyghur control groups than in Han control groups (P ≤ 0.05). (2) The frequency of HLA-A*01:01 in patients was significantly higher than controls. In contrast, the frequencies of HLA-A*30:01 and HLA-A*33:03 were lower in patients (P ≤ 0.05). (3) The frequency of HLA-A*30:01 in Han patients was lower than Han control group (P ≤ 0.05). However, there was no statistically significant in the frequency of HLA-A between Uyghur patients and controls (P > 0.05). (4) There was no significant association between HLA-A alleles and HPV16 or squamous cell carcinoma antigen levels (P > 0.05). (5) The frequency of HLA-A*30:01 allele in complete response + partial response group was higher than stable disease + progressive disease group (P ≤ 0.05).
Conclusions: People from two ethnic groups displayed different HLA-A gene distribution. HLA-A*30:01 and HLA-A*33:03 alleles are the protective factors to cervical cancer patients from Xinjiang while HLA-A*01:01 serves as the susceptible gene.

Yang Y, Bhosle SR, Yu YH, et al.
Tumidulin, a Lichen Secondary Metabolite, Decreases the Stemness Potential of Colorectal Cancer Cells.
Molecules. 2018; 23(11) [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Lichens produce various unique chemicals that are used in the pharmaceutical industry. To screen for novel lichen secondary metabolites that inhibit the stemness potential of colorectal cancer cells, we tested acetone extracts of 11 lichen samples collected in Chile. Tumidulin, isolated from

Duffy DL, Zhu G, Li X, et al.
Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.
Nat Commun. 2018; 9(1):4774 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

Zhao J, Wang YL, Li XB, et al.
Comparative analysis of the diffusion kurtosis imaging and diffusion tensor imaging in grading gliomas, predicting tumour cell proliferation and IDH-1 gene mutation status.
J Neurooncol. 2019; 141(1):195-203 [PubMed] Related Publications
INTRODUCTION: Few studies have applied diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) for the comprehensive assessment of gliomas [tumour grade, isocitrate dehydrogenase-1 (IDH-1) mutation status and tumour proliferation rate (Ki-67)]. This study describes the efficacy of DKI and DTI to comprehensively evaluate gliomas, compares their results.
METHODS: Fifty-two patients (18 females; median age, 47.5 years) with pathologically proved gliomas were prospectively included. All cases underwent DKI examination. DKI (mean kurtosis: MK, axial kurtosis: Ka, radial kurtosis: Kr) and DTI (mean diffusivity: MD, fractional anisotropy: FA) maps of each metric was derived. Three ROIs were manually drawn.
RESULTS: MK, Ka, Kr and FA were significantly higher in HGGs than in LGGs, whereas MD was significantly lower in HGGs than in LGGs (P < 0.01). ROC analysis demonstrated that MK (specificity: 100% sensitivity: 79%) and Ka (specificity: 96% sensitivity: 82%) had the same and highest (AUC: 0.93) diagnostic value. Moreover, MK, Ka, and Kr were significantly higher in grade III than II gliomas (P ≦ 0.01). Further, DKI and DTI can significantly identify IDH-1 mutation status (P ≦ 0.03). Ka (sensitivity: 74%, specificity: 75%, AUC: 0.72) showed the highest diagnostic value. In addition, DKI metrics and MD showed significant correlations with Ki-67 (P ≦ 0.01) and Ka had the highest correlation coefficient (r
CONCLUSIONS: Compared with DTI, DKI has great advantages for the comprehensive assessment of gliomas. Ka might serve as a promising imaging index in predicting glioma grading, tumour cell proliferation rate and IDH-1 gene mutation status.

Zhang T, Choi J, Kovacs MA, et al.
Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes.
Genome Res. 2018; 28(11):1621-1635 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335

Bofinger R, Zaw-Thin M, Mitchell NJ, et al.
Development of lipopolyplexes for gene delivery: A comparison of the effects of differing modes of targeting peptide display on the structure and transfection activities of lipopolyplexes.
J Pept Sci. 2018; 24(12):e3131 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
The design, synthesis and formulation of non-viral gene delivery vectors is an area of renewed research interest. Amongst the most efficient non-viral gene delivery systems are lipopolyplexes, in which cationic peptides are co-formulated with plasmid DNA and lipids. One advantage of lipopolyplex vectors is that they have the potential to be targeted to specific cell types by attaching peptide targeting ligands on the surface, thus increasing both the transfection efficiency and selectivity for disease targets such as cancer cells. In this paper, we have investigated two different modes of displaying cell-specific peptide targeting ligands at the surface of lipopolyplexes. Lipopolyplexes formulated with bimodal peptides, with both receptor binding and DNA condensing sequences, were compared with lipopolyplexes with the peptide targeting ligand directly conjugated to one of the lipids. Three EGFR targeting peptide sequences were studied, together with a range of lipid formulations and maleimide lipid structures. The biophysical properties of the lipopolyplexes and their transfection efficiencies in a basal-like breast cancer cell line were investigated using plasmid DNA bearing genes for the expression of firefly luciferase and green fluorescent protein. Fluorescence quenching experiments were also used to probe the macromolecular organisation of the peptide and pDNA components of the lipopolyplexes. We demonstrated that both approaches to lipopolyplex targeting give reasonable transfection efficiencies, and the transfection efficiency of each lipopolyplex formulation is highly dependent on the sequence of the targeting peptide. To achieve maximum therapeutic efficiency, different peptide targeting sequences and lipopolyplex architectures should be investigated for each target cell type.

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