Gene Summary

Gene:NR3C1; nuclear receptor subfamily 3 group C member 1
Summary:This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175). [provided by RefSeq, Feb 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:glucocorticoid receptor
Source:NCBIAccessed: 16 March, 2017


What does this gene/protein do?
Show (51)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Adolescents
  • Cancer Gene Expression Regulation
  • Acute Lymphocytic Leukaemia
  • Epigenetics
  • Cluster Analysis
  • Chromatin Immunoprecipitation
  • Prostate Cancer
  • Base Sequence
  • Genotype
  • Stomach Cancer
  • Tumor Suppressor Proteins
  • Polymorphism
  • Oligonucleotide Array Sequence Analysis
  • Cancer DNA
  • Chromosome 5
  • Multiple Myeloma
  • Single Nucleotide Polymorphism
  • Sex Characteristics
  • Signal Transduction
  • Neoplasm Recurrence, Local
  • Ubiquitin-Conjugating Enzymes
  • Up-Regulation
  • Genetic Predisposition
  • Protein Binding
  • Oncogene Fusion Proteins
  • Glucocorticoids
  • Dexamethasone
  • DNA Methylation
  • Transcription
  • Tyramine
  • Infant
  • Childhood Cancer
  • Drug Resistance
  • Gene Expression Profiling
  • Polymerase Chain Reaction
  • Messenger RNA
  • Glucocorticoid Receptors
  • Promoter Regions
  • Mutation
  • Molecular Sequence Data
  • Biomarkers, Tumor
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NR3C1 (cancer-related)

Galanopoulos M, Papanikolaou IS, Zografos E, et al.
Comparative Study of Mutations in Single Nucleotide Polymorphism Loci of KRAS and BRAF Genes in Patients Who Underwent Screening Colonoscopy, With and Without Premalignant Intestinal Polyps.
Anticancer Res. 2017; 37(2):651-657 [PubMed] Related Publications
AIM: Our aim was to perform a comparison study of the mutation rate of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), and v-Raf murine sarcoma viral oncogene homolog-B (BRAF) genes between blood-based cell-free DNA (cfDNA), and tissue sample biopsies in individuals undergoing screening colonoscopy.
MATERIALS AND METHODS: All specimens were collected from January 2015 to January 2016. A total of 92 blood samples and colonic biopsy specimens were collected from healthy individuals with no polyps undergoing screening colonoscopy (group A, n=35), patients with colorectal cancer (group B, n=27), and patients with neoplastic intestinal polyps (group C, n=30). Peripheral blood was collected from each patient and a focal tissue biopsy was conducted.
RESULTS: We only found a limited statistically significant difference (p=0.046) in the mutation analysis for codon 12 of the KRAS gene when we compared tissue biopsies from patients in group B to those from group C. In the blood samples, only the rate of mutation in codon 12 of the KRAS gene in samples of group B was significantly higher than that in group A (p=0.013).
CONCLUSION: Blood cfDNA may be a promising tool in CRC screening as it may discriminate patients with CRC compared to healthy individuals and those with colonic polyps, even though it does not appear useful in predicting the presence of colonic polyps.

Koukkou EG, Roupas ND, Markou KB
Effect of excess iodine intake on thyroid on human health.
Minerva Med. 2017; 108(2):136-146 [PubMed] Related Publications
The recommended daily intake of iodide, is 150 μg for adolescents and adults, 250 μg for pregnancy and lactation. Thyroid gland is an effective collector of iodine. The active iodine uptake along the basolateral membrane of thyroid cell is followed by its transport to the apical edge of the cell and then to the follicle lumen. TSH acts through cAMP and stimulates NIS gene expression and protein synthesis. The major proportion of iodine in the thyroid gland is bound to Thyroglobulin. The non-organic intrathyroidal iodine is usually low, but significantly greater compared to plasma. Large doses of iodine reduce both the uptake and the organification (Wolff-Chaikoff effect) and cause partial inhibition of Tg proteolysis. The thyroid gland has several protective mechanisms resulting on the maintenance of normal thyroid function despite wide fluctuations of the daily iodine intake. Ingestion of several commonly used drugs and food conservatives results in acute or chronic excessive iodine intake. Failure to escape from the iodine induced organification inhibition can cause hypothyroidism, which is temporary and subsides after iodine exposure ceases. Iodine excess may also establish a status of excessive thyroid hormone synthesis and release, thus inducing autonomic thyroid function in iodopenic areas or can contribute to the development of iodine-induced hyperthyroidism in iodine abundant areas. The anti-arrhythmic Amiodarone, is a benzofuranic product with a very high iodine content, is associated with either hypo- or hyperthyroidism development. In the presence of defective auto-protective mechanisms, excessive iodine ingestion can divert the normal thyroid function.

Damaskos C, Valsami S, Kontos M, et al.
Histone Deacetylase Inhibitors: An Attractive Therapeutic Strategy Against Breast Cancer.
Anticancer Res. 2017; 37(1):35-46 [PubMed] Related Publications
With a lifetime risk estimated to be one in eight in industrialized countries, breast cancer is the most frequent type of cancer among women worldwide. Patients are often treated with anti-estrogens, but it is common that some tumors develop resistance to therapy. The causation and progression of cancer is controlled by epigenetic processes, so there is an ongoing interest in research into mechanisms, genes and signaling pathways associating carcinogenesis with epigenetic modulation of gene expression. Given the fact that histone deacetylases (HDACs) have a great impact on chromatin remodeling and epigenetics, their inhibitors have become a very interesting field of research.
AIM: This review focused on the use of HDAC inhibitors as anticancer treatment and explains the mechanisms of therapeutic effects on breast cancer. We anticipate further clinical benefits of this new class of drugs, both as single agents and in combination therapy. Molecules such as suberoylanilide hydroxamic acid, trichostatin A, suberoylbis-hydroxamic acid, panobinostat, entinostat, valproic acid, sodium butyrate, SK7041, FTY720, N-(2-hydroxyphenyl)-2-propylpentanamide, Scriptaid, YCW1, santacruzamate A and ferrocenyl have shown promising antitumor effects against breast cancer. HDAC inhibitors consists an attractive field for targeted therapy against breast cancer. Future therapeutic strategies will include combination of HDAC inhibitors and chemotherapy or other inhibitors, in order to target multiple oncogenic signaling pathways. More trials are needed.

Armakolas N, Armakolas A, Antonopoulos A, et al.
The role of the IGF-1 Ec in myoskeletal system and osteosarcoma pathophysiology.
Crit Rev Oncol Hematol. 2016; 108:137-145 [PubMed] Related Publications
Growth hormone (GH) regulated mainly liver-produced insulin-like growth factor 1 (IGF-1) is a key molecule in embryonic & post embryonic development that is also involved in cancer biology. Herein we review new insights of the role of igf-1 gene products and of the IGF-1Ec isoform in muscle and bone development/repair and its role in osteosarcoma pathophysiology, underlying the possible role of the Ec peptide as a future therapeutic target.

Pectasides D, Kotoula V, Papaxoinis G, et al.
Expression Patterns of Growth and Survival Genes with Prognostic Implications in Advanced Pancreatic Cancer.
Anticancer Res. 2016; 36(12):6347-6356 [PubMed] Related Publications
AIM: The aim of this study was to evaluate the mRNA expression pattern of growth- and survival-related genes and assess their prognostic significance in patients with advanced pancreatic cancer.
PATIENTS AND METHODS: In total, 98 patients were included in this retrospective translational research study and were evaluated for Kirsten rat sarcoma viral oncogene homolog (KRAS) mutational status, and v-akt murine thymoma viral oncogene homolog 1 (AKT1), AKT serine/threonine kinase 2 (AKT2), AKT serine/threonine kinase 3 (AKT3), cyclin D1 (CCND1), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), hepatocellular growth factor receptor (MET), avian myelomatosis viral oncogene homolog (MYC), nuclear factor kappa B subunit 1 (NFKb1), phosphatase and tensin homolog (PTEN) and mechanistic target of rapamycin (FRAP1) genes mRNA expression. Among these patients, 73 received first-line gemcitabine combined with erlotinib (N=57) or gefitinib (N=16).
RESULTS: KRAS mutation did not correlate with mRNA gene expression. Unsupervised hierarchical clustering according to mRNA gene expression successfully distinguished four prognostically distinct groups of tumors. Overexpression of all genes was associated with best prognosis, while suppression or heterogeneous expression patterns of the examined genes were associated with expression patterns of growth- and survival-related genes, classifying pancreatic tumors into distinct groups with possibly different outcomes.

Damaskos C, Valsami S, Spartalis E, et al.
Histone Deacetylase Inhibitors: A Novel Therapeutic Weapon Against Medullary Thyroid Cancer?
Anticancer Res. 2016; 36(10):5019-5024 [PubMed] Related Publications
BACKGROUND/AIM: Medullary thyroid cancer (MTC) is highly malignant, metastatic and recurrent, remaining generally incurable, and responsible for approximately 14% of all thyroid carcinoma-related deaths. MTC can metastasize to lymph nodes, trachea and distant organs, such as brain, lungs, liver and bones. MTC cells are resistant to chemotherapy and traditional external therapies are not showing definite clinical benefits. Scientists are trying to understand the molecular background of carcinogenesis and histone deacetylase (HDAC) seems to play a potential role to gene transcription. On the other hand, HDAC inhibitors (HDACI) hamper the HDAC action giving promising results as new anticancer drugs. The purpose of this review was to evaluate the current status of research considering the role of HDACIs in MTC treatment and to present the latest trends in MTC treatment protocols.
MATERIALS AND METHODS: This literature review was accomplished using the MEDLINE database. The key words/phrases were; HDACI, medullary thyroid cancer, HDACI in the therapy of neuroendocrine tumors, HDACI in MTC. Forty-one articles were selected from the total number of the search's results. Only sixteen papers focus on the use of HDACIs in the treatment of MTC. In order to extract our conclusions, we took into account some studies whose main topic does not strictly refer to the MTC but they contain noteworthy and useful information. Only English articles published up to August 2016 were assessed and used for writing this review.
RESULTS: Molecules, such as valproid acid (VPA), vorinostat, suberoyl bis-hydroxamic acid (SBHA), depsipeptide, belinostat, m-carboxycinnamic acid bis-hydroxamine (CBHA) and AB3 have shown promising antitumor effects against MTC.
CONCLUSION: HDACIs represent a promising field for targeted therapy both for its anticancer properties, as well as for augmenting radiotherapeutic modalities. More trials are needed.

Bubendorf L, Büttner R, Al-Dayel F, et al.
Testing for ROS1 in non-small cell lung cancer: a review with recommendations.
Virchows Arch. 2016; 469(5):489-503 [PubMed] Free Access to Full Article Related Publications
Rearrangements of the ROS1 gene occur in 1-2 % of non-small cell lung cancers (NSCLCs). Crizotinib, a highly effective inhibitor of ROS1 kinase activity, is now FDA-approved for the treatment of patients with advanced ROS1-positive NSCLC. Consequently, focus on ROS1 testing is growing. Most laboratories currently rely on fluorescence in situ hybridisation (FISH) assays using a dual-colour break-apart probe to detect ROS1 rearrangements. Given the rarity of these rearrangements in NSCLC, detection of elevated ROS1 protein levels by immunohistochemistry may provide cost-effective screening prior to confirmatory FISH testing. Non-in situ testing approaches also hold potential as stand-alone methods or complementary tests, including multiplex real-time PCR assays and next-generation sequencing (NGS) platforms which include commercial test kits covering a range of fusion genes. In order to ensure high-quality biomarker testing, appropriate tissue handling, adequate control materials and participation in external quality assessment programmes are essential, irrespective of the testing technique employed. ROS1 testing is often only considered after negative tests for EGFR mutation and ALK gene rearrangement, based on the assumption that these oncogenic driver events tend to be exclusive. However, as the use of ROS1 inhibitors becomes routine, accurate and timely detection of ROS1 gene rearrangements will be critical for the optimal treatment of patients with NSCLC. As NGS techniques are introduced into routine diagnostic practice, ROS1 fusion gene testing will be provided as part of the initial testing package.

Rapti SM, Kontos CK, Papadopoulos IN, Scorilas A
High miR-96 levels in colorectal adenocarcinoma predict poor prognosis, particularly in patients without distant metastasis at the time of initial diagnosis.
Tumour Biol. 2016; 37(9):11815-11824 [PubMed] Related Publications
MicroRNA-96 (miR-96) is an oncomiR that facilitates the development of malignant tumors by promoting growth, proliferation, and survival of cancer cells. Previous studies using high-throughput techniques have shown that miR-96 is upregulated in colorectal cancer compared to adjacent normal colorectal tissue. The aim of this study was the investigation of the potential clinical value of miR-96 as a molecular prognostic biomarker in colorectal adenocarcinoma. For this purpose, total RNA was extracted from 108 primary colorectal adenocarcinoma samples and 54 paired non-cancerous colorectal tissue specimens. After polyadenylation and reverse transcription, miR-96 molecules were determined using an in-house developed real-time quantitative PCR based on SYBR Green chemistry. Calculations were carried out with the comparative CT method, using SNORD48 as endogenous reference gene. Finally, extensive biostatistical analysis was performed and showed that miR-96 is significantly upregulated in colorectal adenocarcinoma specimens compared to their non-cancerous counterparts (p < 0.001) as well as in tumors having invaded regional lymph nodes (p = 0.009) and those of advanced TNM stage (p = 0.008). miR-96 expression is an unfavorable prognostic marker in colorectal adenocarcinoma, predicting poor disease-free and overall survival (p = 0.041 and 0.028, respectively), independently of classical clinicopathological parameters. Most importantly, miR-96 expression stratifies patients without distant metastasis (M0) at the time of diagnosis into two groups with substantially different prognosis (p = 0.040). In conclusion, high tissue levels of miR-96 are associated with advanced stages of colorectal adenocarcinoma and predict an increased risk for disease recurrence and poor overall survival, especially in patients without distant metastasis at the time of diagnosis.

Hegde SM, Kumar MN, Kavya K, et al.
Interplay of nuclear receptors (ER, PR, and GR) and their steroid hormones in MCF-7 cells.
Mol Cell Biochem. 2016; 422(1-2):109-120 [PubMed] Related Publications
Steroid hormones and their nuclear receptors play a major role in the development and progression of breast cancer. MCF-7 cells are triple-positive breast cancer cells expressing estrogen receptor (ER), progesterone receptor (PR), and glucocorticoid receptor (GR). However, interaction and their role in expression pattern of activator protein (AP-1) transcription factors (TFs) are not completely understood. Hence, in our study, MCF-7 cells were used as an in vitro model system to study the interplay between the receptors and hormones. MCF-7 cells were treated with estradiol-17β (E2), progesterone (P4), and dexamethasone (Dex), alone or in combination, to study the proliferation of cells and expression of AP-1 genes. MTT assay results show that E2 or P4 induced the cell proliferation by more than 35 %, and Dex decreased the proliferation by 26 %. E2 and P4 are found to increase ERα by more than twofold and c-Jun, c-Fos, and Fra-1 AP-1 TFs by more than 1.7-fold, while Dex shows opposite effect of E2- or P4-induced effect as well as effect on the expression of nuclear receptors and AP-1 factors. E2 antagonist Fulvestrant (ICI 182,780) found to reduce proliferation and E2-induced expression of AP1-TFs, while P4 or Dex antagonist Mifepristone (RU486) is found to block GR-mediated expression of NRs and AP-1 mRNAs. Results suggest that E2 and P4 act synergistically, and Dex acts as an antagonist of E2 and P4.

Yapijakis C, Adamopoulou M, Tasiouka K, et al.
Mutation Screening of Her-2, N-ras and Nf1 Genes in Brain Tumor Biopsies.
Anticancer Res. 2016; 36(9):4607-11 [PubMed] Related Publications
BACKGROUND/AIM: A deeper understanding of the complex molecular pathology of brain malignancies is needed in order to develop more effective and targeted therapies of these highly lethal disorders. In an effort to further enlighten the molecular pathology of brain oncogenesis involving the her-2 (erbB-2/neu/ngl)/N-ras/nf1 pathway, we screened the genotypes of specimens from various types of brain tumors.
MATERIALS AND METHODS: The studied specimens included 35 biopsies of four general categories: 13 neuroglial tumors (4 astrocytomas, 2 oligodendrogliomas, 7 glioblastomas multiforme), 14 meningiomas, 3 other nervous system tumors (2 schwannomas, 1 craniopharyngioma) and 5 metastatic tumors (such as lung carcinomas and chronic myelocytic leukemia). Screening for most common mutations in oncogenes her-2, N-ras and tumor suppressor gene nf1 was conducted with molecular hybridization techniques (Southern blotting, dot blot and single-strand conformational polymorphism (SSCP) analysis, respectively), and was confirmed by DNA sequencing.
RESULTS: Gene amplification of her-2 was observed in only two cases (6%), namely in one glioblastoma and in one meningioma. Screening of 3 hot spot codons of the N-ras gene (12, 13 and 61) and subsequent DNA sequencing revealed mutations in 19 biopsies encompassing all categories (54%). Screening for mutations in exons of the nf1 gene by SSCP analysis detected a novel nonsense mutation in exon 31 in a unique case of a glioblastoma biopsy (3%) taken from a patient without neurofibromatosis type I.
CONCLUSION: Activated N-ras appears to be a major oncogene in brain oncogenesis, exhibiting the most important role in the her-2/N-ras/nf1 pathway.

Papadavid E, Braoudaki M, Bourdakou M, et al.
Aberrant microRNA expression in tumor mycosis fungoides.
Tumour Biol. 2016; 37(11):14667-14675 [PubMed] Related Publications
Herein, miRNA candidates relevant to mycosis fungoides were investigated to provide data on the molecular mechanisms underlying the pathogenesis of the disease. The miRNA expression profile of skin biopsies from patients with tumor stage MF (tMF) and normal donors was compared using miRNA microarrays. Overall, 154 miRNAs were found differentially expressed between tMF and the control cohort with the majority of them being up-regulated (57 %). Among the upregulated miRNAs, miR-3177, miR-514b-3p, miR-1267, and miR-1282 were exclusively detected in 70 % of tMF. Additional upregulated miRNAs included miR-34a, miR-29a, let-7a*, and miR-210, while miR-200c* was identified among the downregulated ones. Quantitative real-time polymerase chain reaction was used to further investigate the expression profiles of miR-34a and miR-29a and validated the overexpression of miR-34a. Enrichment studies revealed that the target genes of the differentially expressed miRNAs were important in several cancer-related signaling pathways. The overlapping relationship of the target genes among tMF, Sezary syndrome, and atopic dermatitis revealed several common and disease-specific genes. Collectively, our study modulated miR-34a as a candidate oncogenic molecule and miR-29a as a putative tumor suppressor highlighting their promising potential in the molecular pathogenesis of tMF.

Yin H, Wang Y, Chen W, et al.
Drug-resistant CXCR4-positive cells have the molecular characteristics of EMT in NSCLC.
Gene. 2016; 594(1):23-29 [PubMed] Related Publications
High expression of Chemokine receptor 4 (CXCR4) is important in tumor invasion, metastasis, drug-resistance and maintenance of stemness in non-small cell lung cancer (NSCLC). We therefore studied the molecular characteristics of drug-resistant CXCR4-positive cells on epithelial-mesenchymal transition (EMT) for the future identification of the tumor cells with the properties of both EMT and stemness. EMT RT(2) Profier PCR Array was performed to determine the expression levels of mRNA genes in A549 with TGF-β1 induced EMT (A549/TGF-β1) and gefitinib-resistant CXCR4-positive cells (A549/GR). TCGA database on the cBio Cancer Genomics Portal website and Gene Network Central (GNC) Pro Tutorial were used to analyze their clinical relevance and pathway interactions. CXCR4 was up-regulated both in TGF-β induced EMT cells and in gefitinib-resistant cells. In 84 mRNA genes related to EMT, 17 mRNA genes were up-regulated in CXCR4-positive population of A549/GR when compared to those in CXCR4 negative fraction, while 66 mRNA genes were up-regulated during TGF-β induced EMT. ITGA5, BMP7, MMP3, VIM, RGS2, ZEB2, TCF3, SNAI2, VCAN, PLEK2, WNT5A, COL3A1, SPARC and FOXC2 were doubly up-regulated during the two biological processes. Kaplan-Meier analysis indicated that the doubly up-regulated ITGA5, RGS2, SNAI2 and PLEK2 mRNA genes were related to poor overall survival in lung adenocarcinoma patients (P=9.291e-6, 0.0090, 3.81e-7 and 0.0013, respectively). In GNC analysis, SNAI2 mRNA gene but not ITGA5, RGS2 and PLEK2 was dependent on the signaling pathway of CXCR4. The molecular characteristics of drug-resistant CXCR4-positive cells have a crosstalk with EMT, which has the potential to find the marker with prognostic value on multiple signaling pathways in NSCLC.

Kotantaki P, Mosialos G
The expression of tumor suppressor gene Cyld is upregulated by histone deacetylace inhibitors in human hepatocellular carcinoma cell lines.
Cell Biochem Funct. 2016; 34(7):465-468 [PubMed] Related Publications
CYLD is a deubiquitinating enzyme that exerts a tumor suppressive function. Its downregulation or inactivation has been associated with the development of several types of malignancies including hepatocellular carcinoma (HCC). HCC cells display significantly lower Cyld expression compared to primary human hepatocytes, and Cyld downregulation can contribute to apoptotic resistance of HCC cells. Little is known about the mechanism of Cyld downregulation in human HCC cells. In the present study we explored the possible regulation of Cyld expression by histone deacetylases (HDACs) in human HCC cell lines. We demonstrated that the HDAC inhibitors suberoylanilide hydroxamic acid, sodium butyrate, and trichostatin A induced the upregulation of both mRNA and protein levels of CYLD in two different HCC cell lines, HepG2 and Huh7. Our results demonstrate the involvement of HDACs in the downregulation of Cyld expression in HCC cells and support and may improve the use of HDAC inhibitors for the treatment for HCC.

Minchenko DO, Riabovol OO, Tsymbal DO, et al.
Inhibition of IRE1 signaling affects the expression of genes encoded glucocorticoid receptor and some related factors and their hypoxic regulation in U87 glioma cells.
Endocr Regul. 2016; 50(3):127-36 [PubMed] Related Publications
OBJECTIVE: The aim of the present investigation was to examine the effect of inhibition of endoplasmic reticulum stress signaling, mediated by IRE1 (inositol requiring enzyme 1), which is a central mediator of the unfolded protein response on the expression of genes encoding glucocorticoid receptor (NR3C1) and some related proteins (SGK1, SGK3, NCOA1, NCOA2, ARHGAP35, NNT) and their hypoxic regulation in U87 glioma cells for evaluation of their possible significance in the control of the glioma growth.
METHODS: The expression of NR3C1,SGK1,SGK3, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells, transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia, was studied by quantitative polymerase chain reaction.
RESULTS: Inhibition of IRE1 signaling enzyme function up-regulates the expression of NR3C1, SGK1, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells in comparison with the control glioma cells, with more significant changes for NR3C1, SGK1, and NNT genes. At the same time, the expression of SGK3 gene is strongly down-regulated in glioma cells upon inhibition of IRE1. We have also shown that hypoxia increases the expression of NR3C1, SGK1, NCOA2, ARHGAP35, and NNT genes but decreases SGK3 and NCOA1 genes expression in control glioma cells. Moreover, the inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in U87 glioma cells enhances the eff ect of hypoxia on the expression of SGK1, SGK3, and NNT genes, but decreases the sensitivity of NR3C1 gene to hypoxic condition. Furthermore, the expression of NCOA1 gene is resistant to hypoxia in control glioma cells, but NCOA2 and ARHGAP35 genes are resistant to this condition in glioma cells without functional activity of IRE1 signaling enzyme.
CONCLUSIONS: Results of this investigation demonstrate that inhibition of IRE1 signaling enzyme function affects the expression of NR3C1, SGK1, SGK3, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells in gene specific manner and that all these genes are regulated by hypoxia preferentially through IRE1 signaling pathway of the endoplasmic reticulum stress.

Parisi C, Mastoraki S, Markou A, et al.
Development and validation of a multiplex methylation specific PCR-coupled liquid bead array for liquid biopsy analysis.
Clin Chim Acta. 2016; 461:156-64 [PubMed] Related Publications
BACKGROUND: Liquid biopsy is based on minimally invasive blood tests and has the potential to characterize the evolution of a solid tumor in real time, by extracting molecular information from circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Epigenetic silencing of tumor and metastasis suppressor genes plays a key role in survival and metastatic potential of cancer cells. Our group was the first to show the presence of epigenetic alterations in CTCs.
METHODS: We present the development and analytical validation of a highly specific and sensitive Multiplex Methylation Specific PCR-coupled liquid bead array (MMSPA) for the simultaneous detection of the methylation status of three tumor and metastasis suppressor genes (CST6, SOX17 and BRMS1) in liquid biopsy material (CTCs, corresponding ctDNA) and paired primary breast tumors.
RESULTS: In the EpCAM-positive CTCs fraction we observed methylation of: a) CST6, in 11/30(37%) and 11/30(37%), b) BRMS1 in 8/30(27%) and 11/30(37%) c) SOX17 in 8/30(27%) and 13/30(43%) early breast cancer patients and patients with verified metastasis respectively. In ctDNA we observed methylation of: a) CST6, in 5/30(17%) and 10/31(32%), b) BRMS1 in 8/30 (27%) and 8/31 (26%) c) SOX17 in 5/30(17%) and 13/31(42%) early breast cancer patients and patients with verified metastasis respectively.
CONCLUSIONS: Our results indicate a high cancerous load at the epigenetic level in EpCAM-positive CTCs fractions and corresponding ctDNA in breast cancer. The main principle of the developed methodology has the potential to be extended in a large number of gene-targets and be applied in many types of cancer.

Wei TT, Lin YT, Chen WS, et al.
Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer.
EBioMedicine. 2016; 10:124-36 [PubMed] Free Access to Full Article Related Publications
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors decreasing serum cholesterol and have shown promise in cancer prevention. In this study, we demonstrated the oncogenic role of HMGR in colorectal cancer (CRC) by disclosing increased HMGR activity in CRC patients and its enhancement of anti-apoptosis and stemness. Our previous studies showed that statins containing carboxylic acid chains possessed activity against histone deacetylases (HDACs), and strengthened their anti-HDAC activity through designing HMGR-HDAC dual inhibitors, JMF compounds. These compounds exerted anti-cancer effect in CRC cells as well as in AOM-DSS and Apc(Min/+) CRC mouse models. JMF mostly regulated the genes related to apoptosis and inflammation through genome-wide ChIP-on-chip analysis, and Ingenuity Pathways Analysis (IPA) predicted their respective regulation by NR3C1 and NF-κB. Furthermore, JMF inhibited metastasis, angiogenesis and cancer stemness, and potentiated the effect of oxaliplatin in CRC mouse models. Dual HMGR-HDAC inhibitor could be a potential treatment for CRC.

Wu Q, Wang X, Liu J, et al.
Nutlin-3 reverses the epithelial-mesenchymal transition in gemcitabine-resistant hepatocellular carcinoma cells.
Oncol Rep. 2016; 36(3):1325-32 [PubMed] Related Publications
Nutlin-3, a small molecule regulator of the tumor suppressor p53, targets the interaction between p53 and murine double minute 2 (MDM2) thereby promoting stabilization of p53 and subsequent p53‑dependent induction of apoptosis and cell cycle arrest. Recent studies have demonstrated that Nutlin‑3 plays a critical role in regulating tumor cell migration, invasion, metastasis, and drug resistance. Although these studies identified various biological functions of Nutlin‑3, our understanding of the exact molecular mechanisms of Nutlin‑3‑mediated antitumor activity remains incomplete. In this study, we elucidated a role of Nutlin‑3 in reversing the epithelial‑mesenchymal transition (EMT) in gemcitabine-resistant (GR) hepatocellular carcinoma (HCC) cells. We assessed the effect of Nutlin‑3 treatment on cell growth, migration, and invasion in both parental HCC cells and GR HCC cells. Moreover, we detected the expression of EMT markers in GR HCC cells treated with Nutlin‑3 by real‑time RT‑PCR and western blot analysis, respectively. We found that Nutlin-3 inhibited cell migration and invasion in the GR HCC cells. Additionally, Nutlin‑3 treatment increased E-cadherin protein levels, but decreased the protein levels of vimentin, Snail and Slug in the GR HCC cells. Furthermore, we found that Smad2 was highly expressed in the GR HCC cells compared with their parental HCC cells, and Nutlin-3 treatment downregulated Smad2 expression in the GR HCC cells. Depletion of Smad2 retarded cell migration and regulated the expression of EMT markers in GR HCC cells similarly to Nutlin‑3 treatment. Our findings highlight an important role of Nutlin‑3 in reversing EMT in GR cells through regulation of Smad2 expression, suggesting that Nutlin-3 could be a potential agent for the treatment of HCC patients with gemcitabine resistance.

Park S, Hong JP, Lee JK, et al.
Associations between the neuron-specific glucocorticoid receptor (NR3C1) Bcl-1 polymorphisms and suicide in cancer patients within the first year of diagnosis.
Behav Brain Funct. 2016; 12(1):22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer diagnosis is associated with an increased suicide risk, particularly within the first 1 year after diagnosis of cancer. Abnormal function of the hypothalamic-pituitary-adrenal axis has been implicated in the pathophysiology of depression and suicide. We examined genetic associations of the functional Bcl-1 polymorphism of (rs41423247) neuron-specific glucocorticoid receptor (NR3C1) gene, with death by suicide in cancer patients. Suicides occurring within a year of cancer diagnosis ('early suicide') were considered separately from those suicides during the second or subsequent year ('late suicide') after cancer diagnosis.
METHODS: The subjects consisted of 343 cancer patients admitted to a general hospital in Seoul, South Korea from 1996 to 2009, of which 182 had died by suicide and 161 were alive on December 31, 2009. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue sample of patients with cancer. We conducted a case-control association analysis of Bcl-1 polymorphism of NR3C1 gene.
RESULTS: Subjects carrying the GG genotype of Bcl-1 polymorphism were at increased risk of early suicide when compared to those carrying the CC genotype (OR 3.80, 95 % CI 1.02-14.16, p = .047). Similarly, those individuals carrying the GG genotype (recessive mode) had an increased risk of early suicide relative to the CC or CG genotype (OR 3.71, 95 % CI 1.03-13.43, p = .045). However, there were no differences in the genotype distributions of the NR3C1 Bcl-1 polymorphism between late suicide cases and controls.
CONCLUSIONS: Our findings suggest that the NR3C1 Bcl-1 polymorphisms may be involved in the susceptibility to suicide within the first year after cancer diagnosis among cancer patients in Korean population.

Liu C, Wu HT, Zhu N, et al.
Steroid receptor RNA activator: Biologic function and role in disease.
Clin Chim Acta. 2016; 459:137-46 [PubMed] Related Publications
Steroid receptor RNA activator (SRA) is a type of long noncoding RNA (lncRNA) which coordinates the functions of various transcription factors, enhances steroid receptor-dependent gene expression, and also serves as a distinct scaffold. The novel, profound and expanded roles of SRA are emerging in critical aspects of coactivation of nuclear receptors (NRs). As a nuclear receptor coactivator, SRA can coactivate androgen receptor (AR), estrogen receptor α (ERα), ERβ, progesterone receptor (PR), glucocorticoid receptor (GR), thyroid hormone receptor and retinoic acid receptor (RAR). Although SRA is one of the least well-understood molecules, increasing studies have revealed that SRA plays a key role in both biological processes, such as myogenesis and steroidogenesis, and pathological changes, including obesity, cardiomyopathy, and tumorigenesis. Furthermore, the SRA-related signaling pathways, such as the mitogen-activated protein kinase (p38 MAPK), Notch and tumor necrosis factor α (TNFα) pathways, play critical roles in the pathogenesis of estrogen-dependent breast cancers. In addition, the most recent data demonstrates that SRA expression may serve as a new prognostic marker in patients with ER-positive breast cancer. Thus, elucidating the molecular mechanisms underlying SRA-mediated functions is important to develop proper novel strategies to target SRA in the diagnosis and treatment of human diseases.

Michailidou M, Giannouli V, Kotsikoris V, et al.
Novel pyrazolopyridine derivatives as potential angiogenesis inhibitors: Synthesis, biological evaluation and transcriptome-based mechanistic analysis.
Eur J Med Chem. 2016; 121:143-57 [PubMed] Related Publications
Modified purine derivatives exemplified by pyrazolopyrimidines have emerged as highly selective inhibitors of several angiogenic receptor tyrosine kinases. Herein, we designed and synthesized a new series of substituted pyrazolopyridines and explored their ability to influence crucial pro-angiogenic attributes of endothelial cells. Four of the synthesized compounds, possessing analogous substitution pattern, were found able to inhibit at low micromolar concentrations endothelial cell proliferation, migration and differentiation, constitutively or in response to Vascular Endothelial Growth Factor (VEGF) and to attenuate VEGF-induced phosphorylation of VEGF receptor-2 and downstream kinases AKT and ERK1/2. Administration of effective compounds in mice delayed the growth of syngeneic Lewis lung carcinoma transplants and reduced tumor microvessel density, without causing toxicity. Genome-wide microarray and gene ontology analyses of treated endothelial cells revealed derivative 18c as the most efficient modulator of gene expression and "mitotic cell cycle/cell division" along with "cholesterol biosynthesis" as the most significantly altered biological processes.

Geng L, Zhu M, Wang Y, et al.
Genetic variants in chromatin-remodeling pathway associated with lung cancer risk in a Chinese population.
Gene. 2016; 587(2):178-82 [PubMed] Related Publications
Chromatin remodeling complexes utilize the energy of ATP hydrolysis to remodel nucleosomes and have essential roles in transcriptional modulation. Increasing evidences indicate that these complexes directly interact with numerous proteins and regulate the formation of cancer. However, few studies reported the association of polymorphisms in chromatin remodeling genes and lung cancer. We hypothesized that variants in critical genes of chromatin remodeling pathway might contribute to the susceptibility of lung cancer. To validate this hypothesis, we systematically screened 40 polymorphisms in six key chromatin remodeling genes (SMARCA5, SMARCC2, SMARCD2, ARID1A, NR3C1 and SATB1) and evaluated them with a case-control study including 1341 cases and 1982 controls. Logistic regression revealed that four variants in NR3C1 and SATB1 were significantly associated with lung cancer risk after false discovery rate (FDR) correction [For NR3C1, rs9324921: odds ratio (OR)=1.23, P for FDR=0.029; rs12521436: OR=0.85, P for FDR=0.040; rs4912913: OR=1.17, P for FDR=0.040; For SATB1, rs6808523: OR=1.33, P for FDR=0.040]. Combing analysis presented a significant allele-dosage tendency for the number of risk alleles and lung cancer risk (Ptrend<0.001). Moreover, expression quantitative trait loci (eQTL) analysis revealed that these two genes were differently expressed between lung tumor and adjacent normal tissues in the database of The Cancer Genome Atlas (TCGA) (P=0.009 for rs6808523). These findings suggested that genetic variants in key chromatin remodeling genes may contribute to lung cancer risk in Chinese population. Further large and well-designed studies are warranted to validate our results.

Zografos E, Gazouli M, Tsangaris G, Marinos E
The Significance of Proteomic Biomarkers in Male Breast Cancer.
Cancer Genomics Proteomics. 2016 May-Jun; 13(3):183-90 [PubMed] Related Publications
Breast cancer in men (MBC) is an uncommon malignancy and accounts for only 1% of all diagnosed breast cancers. By using genomic and transcriptomic approaches, researchers have been able to expand our insight into the genetic basis of breast cancer, by providing new biomarkers. We currently know that gene analysis by itself does not show the complete picture. Along with the genomic approach, proteomics are crucial for the improvement of breast cancer diagnosis, sub-classification, for predicting response to different treatment modalities and for predicting prognosis. There are great challenges in identifying discriminatory proteins and the use of specific techniques along with additional analytical tools is required. A number of techniques allow testing for proteins produced during specific diseases. In this review, an effort is made to summarize the studies and results linked to the implementation of proteomics in the field of MBC detection and diagnosis.

Lim SL, Mustapha NM, Goh YM, et al.
Metastasized lung cancer suppression by Morinda citrifolia (Noni) leaf compared to Erlotinib via anti-inflammatory, endogenous antioxidant responses and apoptotic gene activation.
Mol Cell Biochem. 2016; 416(1-2):85-97 [PubMed] Related Publications
Metastasized lung and liver cancers cause over 2 million deaths annually, and are amongst the top killer cancers worldwide. Morinda citrifolia (Noni) leaves are traditionally consumed as vegetables in the tropics. The macro and micro effects of M. citrifolia (Noni) leaves on metastasized lung cancer development in vitro and in vivo were compared with the FDA-approved anti-cancer drug Erlotinib. The extract inhibited the proliferation and induced apoptosis in A549 cells (IC50 = 23.47 μg/mL) and mouse Lewis (LL2) lung carcinoma cells (IC50 = 5.50 μg/mL) in vitro, arrested cancer cell cycle at G0/G1 phases and significantly increased caspase-3/-8 without changing caspase-9 levels. The extract showed no toxicity on normal MRC5 lung cells. Non-small-cell lung cancer (NSCLC) A549-induced BALB/c mice were fed with 150 and 300 mg/kg M. citrifolia leaf extract and compared with Erlotinib (50 mg/kg body weight) for 21 days. It significantly increased the pro-apoptotic TRP53 genes, downregulated the pro-tumourigenesis genes (BIRC5, JAK2/STAT3/STAT5A) in the mice tumours, significantly increased the anti-inflammatory IL4, IL10 and NR3C1 expression in the metastasized lung and hepatic cancer tissues and enhanced the NFE2L2-dependent antioxidant responses against oxidative injuries. The extract elevated serum neutrophils and reduced the red blood cells, haemoglobin, corpuscular volume and cell haemoglobin concentration in the lung cancer-induced mammal. It suppressed inflammation and oedema, and upregulated the endogenous antioxidant responses and apoptotic genes to suppress the cancer. The 300 mg/kg extract was more effective than the 50 mg/kg Erlotinib for most of the parameters measured.

Rai R, Kim JJ, Tewari M, Shukla HS
Heterogeneous expression of cholecystokinin and gastrin receptor in stomach and pancreatic cancer: An immunohistochemical study.
J Cancer Res Ther. 2016 Jan-Mar; 12(1):411-6 [PubMed] Related Publications
AIM: Cholecystokinin (CCK) and gastrin (Gs) are a well known trophic factor for the gastrointestinal tract and their trophic effects are shown mainly toward pancreas and stomach, respectively. Though, the exact characterization of CCK and Gs receptors subtype (cholecystokinin type A receptor [CCKAR] and cholecystokinin type B receptor/gastrin receptor [CCKBR/GR]) in stomach cancer (SC) and pancreatic cancer (PC) is still controversial and necessities further validation.
SUBJECTS AND METHODS: CCKAR and CCKBR/GR expression was analyzed by immunohistochemistry in 55 SC, 25 benign gastric diseases (BGDs), 38 PC (including periampullary carcinoma), and 10 normal pancreatic tissue. The results were statistically correlated with the patient's clinical history to observe the prognostic significance if any.
RESULT: CCKAR expression was detected in 18.2% of SC, 20% of BGD, 65.8% of PC, and 30.0% of normal pancreas tissue samples. The CCKBR/GR expression was detected in 58.2% of SC, 48.0% of BGD, 18.4% of PC, and 60.0% of normal pancreas tissue samples. CCKBR/GR expression was significantly high in well and moderately differentiated SC samples as compared to poorly differentiated samples.
CONCLUSION: Our study showed significantly higher expression of CCKAR and down regulation of CCKBR in PC as compared to control while CCKBR/GR was detected in majority of SC samples. Thus, our study suggests that CCK and Gs receptors may have diagnostic and therapeutic implications. However, study need to be validated in significantly bigger sample size and need to be replicated in different cohorts.

Putnam CD, Srivatsan A, Nene RV, et al.
A genetic network that suppresses genome rearrangements in Saccharomyces cerevisiae and contains defects in cancers.
Nat Commun. 2016; 7:11256 [PubMed] Free Access to Full Article Related Publications
Gross chromosomal rearrangements (GCRs) play an important role in human diseases, including cancer. The identity of all Genome Instability Suppressing (GIS) genes is not currently known. Here multiple Saccharomyces cerevisiae GCR assays and query mutations were crossed into arrays of mutants to identify progeny with increased GCR rates. One hundred eighty two GIS genes were identified that suppressed GCR formation. Another 438 cooperatively acting GIS genes were identified that were not GIS genes, but suppressed the increased genome instability caused by individual query mutations. Analysis of TCGA data using the human genes predicted to act in GIS pathways revealed that a minimum of 93% of ovarian and 66% of colorectal cancer cases had defects affecting one or more predicted GIS gene. These defects included loss-of-function mutations, copy-number changes associated with reduced expression, and silencing. In contrast, acute myeloid leukaemia cases did not appear to have defects affecting the predicted GIS genes.

Tserga A, Chatziandreou I, Michalopoulos NV, et al.
Mutation of genes of the PI3K/AKT pathway in breast cancer supports their potential importance as biomarker for breast cancer aggressiveness.
Virchows Arch. 2016; 469(1):35-43 [PubMed] Related Publications
Deregulation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is closely associated with cancer development and cancer progression. PIK3CA, AKT1, and PTEN are the fundamental molecules of the PI3K/AKT pathway with increased mutation rates in cancer cases leading to aberrant regulation of the pathway. Even though molecular alterations of the PI3K/AKT pathway have been studied in breast cancer, correlations between specific molecular alterations and clinicopathological features remain contradictory. In this study, we examined mutations of the PI3K/AKT pathway in 75 breast carcinomas using high-resolution melting analysis and pyrosequencing, in parallel with analysis of relative expression of PIK3CA and AKT2 genes. Mutations of PIK3CA were found in our cohort in 21 cases (28 %), 10 (13 %) in exon 9 and 11(15 %) in exon 20. Mutation frequency of AKT1 and PTEN genes was 4 and 3 %, respectively. Overall, alterations in the PI3K/AKT signaling cascade were detected in 35 % of the cases. Furthermore, comparison of 50 breast carcinomas with adjacent normal tissues showed elevated PIK3CA messenger RNA (mRNA) levels in 18 % of tumor cases and elevated AKT2 mRNA levels in 14 %. Our findings, along with those of previous studies, underline the importance of the PI3K/AKT pathway components as potential biomarkers for breast carcinogenesis.

Tesikova M, Dezitter X, Nenseth HZ, et al.
Divergent Binding and Transactivation by Two Related Steroid Receptors at the Same Response Element.
J Biol Chem. 2016; 291(22):11899-910 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
Transcription factor (TF) recruitment to chromatin is central to activation of transcription. TF-chromatin interactions are highly dynamic, which are evaluated by recovery half time (t1/2) in seconds, determined by fluorescence recovery experiments in living cells, and chromatin immunoprecipitation (ChIP) analysis, measured in minutes. These two states are related: the larger the t1/2, the longer the ChIP occupancy resulting in increased transcription. Here we present data showing that this relationship does not always hold. We found that histone deacetylase inhibitors (HDACis) significantly increased t1/2 of green fluorescent protein (GFP) fused androgen receptor (AR) on a tandem array of positive hormone response elements (HREs) in chromatin. This resulted in increased ChIP signal of GFP-AR. Unexpectedly, however, transcription was inhibited. In contrast, the GFP-fused glucocorticoid receptor (GR), acting through the same HREs, displayed a profile consistent with current models. We provide evidence that these differences are mediated, at least in part, by HDACs. Our results provide insight into TF action in living cells and show that very closely related TFs may trigger significantly divergent outcomes at the same REs.

Tanaka Y, Ito S, Isobe K
Vancomycin-sensitive bacteria trigger development of colitis-associated colon cancer by attracting neutrophils.
Sci Rep. 2016; 6:23920 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
Inflammatory bowel disease confers an increased risk of developing colitis-associated colon cancer (CAC). During the active colitis or developing tumor stage, commensal bacteria show dynamic translocation. However, whether alteration of the bacterial composition in the gut causes CAC is still unclear. To clarify the effect of commensal bacteria on CAC development, we employed an azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced murine CAC model treated with or without antibiotics. In addition, we analyzed the effects of antibiotics on infiltration of myeloid cells, colonic inflammatory responses, and colorectal cancer formation. We found that vancomycin treatment dramatically suppressed tumor development. In addition, AOM/DSS treatment greatly induced the infiltration of Gr-1(high)/CD11b(high) neutrophils to the colon, which led to the production of tumor necrosis factor α and inducible nitric oxide synthase. Vancomycin treatment suppressed the infiltration of neutrophils induced by AOM/DSS. Moreover, vancomycin treatment greatly reduced the colon injury and DNA damage caused by AOM/DSS-induced NO radicals. Our results indicate that vancomycin-sensitive bacteria induced colon inflammation and DNA damage by attracting neutrophils into damaged colon tissue, thus promoting tumor formation.

El Ghorayeb N, Rondeau G, Latour M, et al.
Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy: Case Report and Review of the Literature.
Medicine (Baltimore). 2016; 95(13):e3180 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic β-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients.

Kypreou KP, Stefanaki I, Antonopoulou K, et al.
Prediction of Melanoma Risk in a Southern European Population Based on a Weighted Genetic Risk Score.
J Invest Dermatol. 2016; 136(3):690-5 [PubMed] Related Publications
Many single nucleotide polymorphisms (SNPs) have been described as putative risk factors for melanoma. The aim of our study was to validate the most prominent genetic risk loci in an independent Greek melanoma case-control dataset and to assess their cumulative effect solely or combined with established phenotypic risk factors on individualized risk prediction. We genotyped 59 SNPs in 800 patients and 800 controls and tested their association with melanoma using logistic regression analyses. We constructed a weighted genetic risk score (GRSGWS) based on SNPs that showed genome-wide significant (GWS) association with melanoma in previous studies and assessed their impact on risk prediction. Fifteen independent SNPs from 12 loci were significantly associated with melanoma (P < 0.05). Risk score analysis yielded an odds ratio of 1.36 per standard deviation increase of the GRSGWS (P = 1.1 × 10(-7)). Individuals in the highest 20% of the GRSGWS had a 1.88-fold increase in melanoma risk compared with those in the middle quintile. By adding the GRSGWS to a phenotypic risk model, the C-statistic increased from 0.764 to 0.775 (P = 0.007). In summary, the GRSGWS is associated with melanoma risk and achieves a modest improvement in risk prediction when added to a phenotypic risk model.

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