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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:mineralocorticoid receptor
Source:NCBIAccessed: 16 March, 2017


What does this gene/protein do?
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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

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: NR3C2 (cancer-related)

Esposito MR, Aveic S, Seydel A, Tonini GP
Neuroblastoma treatment in the post-genomic era.
J Biomed Sci. 2017; 24(1):14 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma is an embryonic malignancy of early childhood originating from neural crest cells and showing heterogeneous biological, morphological, genetic and clinical characteristics. The correct stratification of neuroblastoma patients within risk groups (low, intermediate, high and ultra-high) is critical for the adequate treatment of the patients.High-throughput technologies in the Omics disciplines are leading to significant insights into the molecular pathogenesis of neuroblastoma. Nonetheless, further study of Omics data is necessary to better characterise neuroblastoma tumour biology. In the present review, we report an update of compounds that are used in preclinical tests and/or in Phase I-II trials for neuroblastoma. Furthermore, we recapitulate a number of compounds targeting proteins associated to neuroblastoma: MYCN (direct and indirect inhibitors) and downstream targets, Trk, ALK and its downstream signalling pathways. In particular, for the latter, given the frequency of ALK gene deregulation in neuroblastoma patients, we discuss on second-generation ALK inhibitors in preclinical or clinical phases developed for the treatment of neuroblastoma patients resistant to crizotinib.We summarise how Omics drive clinical trials for neuroblastoma treatment and how much the research of biological targets is useful for personalised medicine. Finally, we give an overview of the most recent druggable targets selected by Omics investigation and discuss how the Omics results can provide us additional advantages for overcoming tumour drug resistance.

Lee CW, Choi SI, Lee SJ, et al.
The Effectiveness of Ferritin as a Contrast Agent for Cell Tracking MRI in Mouse Cancer Models.
Yonsei Med J. 2017; 58(1):51-58 [PubMed] Free Access to Full Article Related Publications
PURPOSE: We aimed to investigate the effectiveness of ferritin as a contrast agent and a potential reporter gene for tracking tumor cells or macrophages in mouse cancer models.
MATERIALS AND METHODS: Adenoviral human ferritin heavy chain (Ad-hFTH) was administrated to orthotopic glioma models and subcutaneous colon cancer mouse models using U87MG and HCT116 cells, respectively. Brain MR images were acquired before and daily for up to 6 days after the intracranial injection of Ad-hFTH. In the HCT116 tumor model, MR examinations were performed before and at 6, 24, and 48 h after intratumoral injection of Ad-hFTH, as well as before and every two days after intravenous injection of ferritin-labeled macrophages. The contrast effect of ferritin in vitro was measured by MR imaging of cell pellets. MRI examinations using a 7T MR scanner comprised a T1-weighted (T1w) spin-echo sequence, T2-weighted (T2w) relaxation enhancement sequence, and T2*-weighted (T2*w) fast low angle shot sequence.
RESULTS: Cell pellet imaging of Ad-hFTH in vitro showed a strong negatively enhanced contrast in T2w and T2*w images, presenting with darker signal intensity in high concentrations of Fe. T2w images of glioma and subcutaneous HCT116 tumor models showed a dark signal intensity around or within the Ad-hFTH tumor, which was distinct with time and apparent in T2*w images. After injection of ferritin-labeled macrophages, negative contrast enhancement was identified within the tumor.
CONCLUSION: Ferritin could be a good candidate as an endogenous MR contrast agent and a potential reporter gene that is capable of maintaining cell labeling stability and cellular safety.

Demerath T, Simon-Gabriel CP, Kellner E, et al.
Mesoscopic imaging of glioblastomas: Are diffusion, perfusion and spectroscopic measures influenced by the radiogenetic phenotype?
Neuroradiol J. 2017; 30(1):36-47 [PubMed] Related Publications
The purpose of this study was to identify markers from perfusion, diffusion, and chemical shift imaging in glioblastomas (GBMs) and to correlate them with genetically determined and previously published patterns of structural magnetic resonance (MR) imaging. Twenty-six patients (mean age 60 years, 13 female) with GBM were investigated. Imaging consisted of native and contrast-enhanced 3D data, perfusion, diffusion, and spectroscopic imaging. In the presence of minor necrosis, cerebral blood volume (CBV) was higher (median ± SD, 2.23% ± 0.93) than in pronounced necrosis (1.02% ± 0.71), pcorr = 0.0003. CBV adjacent to peritumoral fluid-attenuated inversion recovery (FLAIR) hyperintensity was lower in edema (1.72% ± 0.31) than in infiltration (1.91% ± 0.35), pcorr = 0.039. Axial diffusivity adjacent to peritumoral FLAIR hyperintensity was lower in severe mass effect (1.08*10(-3) mm(2)/s ± 0.08) than in mild mass effect (1.14*10(-3) mm(2)/s ± 0.06), pcorr = 0.048. Myo-inositol was positively correlated with a marker for mitosis (Ki-67) in contrast-enhancing tumor, r = 0.5, pcorr = 0.0002. Changed CBV and axial diffusivity, even outside FLAIR hyperintensity, in adjacent normal-appearing matter can be discussed as to be related to angiogenesis pathways and to activated proliferation genes. The correlation between myo-inositol and Ki-67 might be attributed to its binding to cell surface receptors regulating tumorous proliferation of astrocytic cells.

Zhang G, Lanigan CP, Goldblum JR, et al.
Automated Bright-Field Dual-Color In Situ Hybridization for MDM2: Interobserver Reproducibility and Correlation With Fluorescence In Situ Hybridization in a Series of Soft Tissue Consults.
Arch Pathol Lab Med. 2016; 140(10):1111-5 [PubMed] Related Publications
CONTEXT: -Atypical lipomatous tumors/well-differentiated liposarcomas contain alterations in the 12q13-15 region resulting in amplification of MDM2 and nearby genes. Identifying MDM2 amplification is a useful ancillary test, as the histologic mimics of atypical lipomatous tumors/well-differentiated liposarcomas have consistently shown a lack of MDM2 amplification.
OBJECTIVE: -To assess the interobserver reproducibility of a bright-field assay for MDM2 amplification (dual-color, dual-hapten in situ hybridization [DDISH]) among reviewers with varying degrees of experience with the assay and to assess the concordance of MDM2 DDISH with MDM2 fluorescence in situ hybridization (FISH).
DESIGN: -In total, 102 cases were assessed in parallel for MDM2 by FISH and DDISH. MDM2 amplification was defined as an MDM2 to chromosome 12 ratio of 2.0 or greater, whereas an MDM2 to chromosome 12 ratio of less than 2 was nonamplified. Fluorescence in situ hybridization was scored in the routine clinical laboratory and DDISH was evaluated by 3 different pathologists blinded to the final diagnosis and FISH results.
RESULTS: -Fluorescence in situ hybridization categorized 27 cases (26%) as MDM2 amplified and 75 cases (74%) as nonamplified; the consensus DDISH diagnosis was 98% concordant with FISH. Agreement between MDM2 DDISH by each reviewer and MDM2 FISH was highly concordant (99%, 98%, and 98%, respectively, for reviewers 1, 2 and 3). The κ agreement of the 3 reviewers scoring DDISH was excellent (κ = 0.949, 0.95, and 0.95, respectively, for reviewers 1, 2, and 3).
CONCLUSIONS: -This study highlights excellent concordance between DDISH and FISH in MDM2 copy number assessment. Moreover, excellent interobserver reproducibility of the DDISH assay was found among reviewers with varying levels of experience evaluating bright-field assays.

Ma S, Ding M, Li J, et al.
Ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma: clinical outcomes and prognostic factors.
J Cancer Res Clin Oncol. 2017; 143(1):131-142 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to evaluate the clinical outcomes of ultrasound-guided percutaneous microwave ablation (US-guided PMWA) for the treatment of hepatocellular carcinoma (HCC) with the analysis of prognostic factors.
MATERIALS AND METHODS: The treatment and survival parameters of 433 patients with HCC (≤10 cm), who met the inclusion criteria and had received US-guided PMWA in Renji Hospital from July 2010 to November 2014, were retrospectively analyzed. Imaging examination (contrast-enhanced CT or MR) and tumor markers (AFP and CA199) 1 month after MWA were used to evaluate the efficacy of US-guided PMWA. SPSS software was used to perform all statistical analyses.
RESULTS: The initial complete ablation (CA) rate was 94.9 % (411/433). Twenty-two patients with incomplete ablation received repeat PMWA, and the total CA rate was up to 98.6 % (427/433). Multiple tumor number, tumor >5 cm in diameter, and higher serum AFP level (>20 ng/ml) were significant unfavorable prognosticators of progression-free survival (PFS). The cumulative 1-, 2-, and 3-year overall survival (OS) rates were 83.5, 66.1, and 58.7 %, respectively (median: 43 months). Tumor >5 cm in diameter and serum AFP >400 ng/ml were significant unfavorable prognosticators of OS.
CONCLUSIONS: PMWA is well tolerated in HCC patients and capable of offering high CA rate. Tumor number, tumor size, and AFP level were significant prognosticators of patients' PFS, whereas tumor size and AFP level were significant prognosticators of OS.

Hellner K, Miranda F, Fotso Chedom D, et al.
Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies.
EBioMedicine. 2016; 10:137-49 [PubMed] Free Access to Full Article Related Publications
Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p<2(-16)), which was not found in patients without cancer (n=108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n=100), and common in BRCA1-BRCA2 mutation carriers (n=71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.

Buchanan PJ, McCloskey KD
CaV channels and cancer: canonical functions indicate benefits of repurposed drugs as cancer therapeutics.
Eur Biophys J. 2016; 45(7):621-633 [PubMed] Free Access to Full Article Related Publications
The importance of ion channels in the hallmarks of many cancers is increasingly recognised. This article reviews current knowledge of the expression of members of the voltage-gated calcium channel family (CaV) in cancer at the gene and protein level and discusses their potential functional roles. The ten members of the CaV channel family are classified according to expression of their pore-forming α-subunit; moreover, co-expression of accessory α2δ, β and γ confers a spectrum of biophysical characteristics including voltage dependence of activation and inactivation, current amplitude and activation/inactivation kinetics. CaV channels have traditionally been studied in excitable cells including neurones, smooth muscle, skeletal muscle and cardiac cells, and drugs targeting the channels are used in the treatment of hypertension and epilepsy. There is emerging evidence that several CaV channels are differentially expressed in cancer cells compared to their normal counterparts. Interestingly, a number of CaV channels also have non-canonical functions and are involved in transcriptional regulation of the expression of other proteins including potassium channels. Pharmacological studies show that CaV canonical function contributes to the fundamental biology of proliferation, cell-cycle progression and apoptosis. This raises the intriguing possibility that calcium channel blockers, approved for the treatment of other conditions, could be repurposed to treat particular cancers. Further research will reveal the full extent of both the canonical and non-canonical functions of CaV channels in cancer and whether calcium channel blockers are beneficial in cancer treatment.

Cresswell GD, Apps JR, Chagtai T, et al.
Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications.
EBioMedicine. 2016; 9:120-9 [PubMed] Free Access to Full Article Related Publications
The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution.

Chen X, Zhu Q, Li B, et al.
Renal cell carcinoma associated with Xp11.2 translocation/TFE gene fusion: imaging findings in 21 patients.
Eur Radiol. 2017; 27(2):543-552 [PubMed] Related Publications
OBJECTIVES: To characterize imaging features of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE gene fusion.
METHODS: Twenty-one patients with Xp11.2/TFE RCC were retrospectively evaluated. Tumour location, size, density, cystic or solid appearance, calcification, capsule sign, enhancement pattern and metastases were assessed.
RESULTS: Fourteen women and seven men were identified with 12 being 25 years old or younger. Tumours were solitary and cystic-solid (76.2 %) masses with a capsule (76.2 %); 90.5 % were located in the medulla. Calcifications and lymph node metastases were each observed in 24 %. On unenhanced CT, tumour attenuation was greater than in normal renal parenchyma (85.7 %). Tumour enhancement was less than in normal renal cortex on all enhanced phases, greater than in normal renal medulla on cortical and medullary phases, but less than in normal renal medulla on delayed phase. On MR, the tumours were isointense on T1WI, heterogeneously hypointense on T2WI and slightly hyperintense on diffusion-weighted imaging.
CONCLUSION: Xp11.2/TFE RCC usually occurs in young women. It is a cystic-solid, hyperdense mass with a capsule. It arises from the renal medulla with enhancement less than in the cortex but greater than in the medulla in all phases except the delayed phase, when it is lower than in the medulla.
KEY POINTS: • Xp11.2/TFE RCC was more prevalent in young women. • On unenhanced CT, Xp11.2/TFE RCC attenuation was greater than in renal parenchyma. • Xp111/2TFE RCC arises primarily from the renal medulla. • Xp11.2/TFE RCC enhancement was less than in the cortex on all phases. • Enhancement was greater than in the medulla in arterial and corticomedullary phase.

Krishnan A, Kaza RK, Vummidi DR
Cross-sectional Imaging Review of Tuberous Sclerosis.
Radiol Clin North Am. 2016; 54(3):423-40 [PubMed] Related Publications
Tuberous sclerosis complex (TSC) is a multisystem, genetic disorder characterized by development of hamartomas in the brain, abdomen, and thorax. It results from a mutation in one of 2 tumor suppressor genes that activates the mammalian target of rapamycin pathway. This article discusses the origins of the disorder, the recently updated criteria for the diagnosis of TSC, and the cross-sectional imaging findings and recommendations for surveillance. Familiarity with the diverse radiological features facilitates diagnosis and helps in treatment planning and monitoring response to treatment of this multisystem disorder.

Wu W, Lin Y, Xiang L, et al.
Low-dose decitabine plus all-trans retinoic acid in patients with myeloid neoplasms ineligible for intensive chemotherapy.
Ann Hematol. 2016; 95(7):1051-7 [PubMed] Related Publications
In our previous in vitro trials, decitabine and all-trans retinoic acid (ATRA) demonstrated synergistic effects on growth inhibition, differentiation, and apoptosis in SHI-1 cells; in K562 cells, ATRA enhanced the effect of decitabine on p16 demethylation, and the combination of the two drugs was found to activate RAR-β expression (p16 and RAR-β are two tumor suppressor genes). On the rationale of our in vitro trials, we used low-dose decitabine and ATRA to treat 31 myeloid neoplasms deemed ineligible for intensive chemotherapy. The regimen consisted of decitabine at the dose of 15 mg/m(2) intravenously over 1 h daily for consecutive 5 days and ATRA at the dose of 20 mg/m(2) orally from day 1 to 28 except day 4 to 28 in the first cycle, and the regimen was repeated every 28 days. After 6 cycles, decitabine treatment was stopped, and ATRA treatment was continued for maintenance treatment. Treated with a median of 2 cycles (range 1-6), 7 patients (22.6 %) achieved complete remission (CR), 7 (22.6 %) marrow CR (mCR), and 4 (12.9 %) partial remission (PR). The overall remission (CR, mCR, and PR) rate was 58.1 %, and the best response (CR and mCR) rate was 45.2 %. The median overall survival (OS) was 11.0 months, the 1-year OS rate was 41.9 %, and the 2-year OS rate was 26.6 %. In univariate analyses, age, performance status, comorbidities, white blood cell counts and platelets at diagnosis, percentage of bone marrow blasts, karyotype, and treatment efficacy demonstrated no impacts on OS (P > 0.05, each). Main side effects were tolerable hematologic toxicities. In conclusion, low-dose decitabine plus ATRA is a promising treatment for patients with myeloid neoplasms judged ineligible for intensive chemotherapy.

Tessem MB, Bertilsson H, Angelsen A, et al.
A Balanced Tissue Composition Reveals New Metabolic and Gene Expression Markers in Prostate Cancer.
PLoS One. 2016; 11(4):e0153727 [PubMed] Free Access to Full Article Related Publications
Molecular analysis of patient tissue samples is essential to characterize the in vivo variability in human cancers which are not accessible in cell-lines or animal models. This applies particularly to studies of tumor metabolism. The challenge is, however, the complex mixture of various tissue types within each sample, such as benign epithelium, stroma and cancer tissue, which can introduce systematic biases when cancers are compared to normal samples. In this study we apply a simple strategy to remove such biases using sample selections where the average content of stroma tissue is balanced between the sample groups. The strategy is applied to a prostate cancer patient cohort where data from MR spectroscopy and gene expression have been collected from and integrated on the exact same tissue samples. We reveal in vivo changes in cancer-relevant metabolic pathways which are otherwise hidden in the data due to tissue confounding. In particular, lowered levels of putrescine are connected to increased expression of SRM, reduced levels of citrate are attributed to upregulation of genes promoting fatty acid synthesis, and increased succinate levels coincide with reduced expression of SUCLA2 and SDHD. In addition, the strategy also highlights important metabolic differences between the stroma, epithelium and prostate cancer. These results show that important in vivo metabolic features of cancer can be revealed from patient data only if the heterogeneous tissue composition is properly accounted for in the analysis.

Yoon RG, Kim HS, Paik W, et al.
Different diagnostic values of imaging parameters to predict pseudoprogression in glioblastoma subgroups stratified by MGMT promoter methylation.
Eur Radiol. 2017; 27(1):255-266 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to determine whether diffusion and perfusion imaging parameters demonstrate different diagnostic values for predicting pseudoprogression between glioblastoma subgroups stratified by O(6)-mythylguanine-DNA methyltransferase (MGMT) promoter methylation status.
METHODS: We enrolled seventy-five glioblastoma patients that had presented with enlarged contrast-enhanced lesions on magnetic resonance imaging (MRI) one month after completing concurrent chemoradiotherapy and undergoing MGMT promoter methylation testing. The imaging parameters included 10 or 90 % histogram cutoffs of apparent diffusion coefficient (ADC10), normalized cerebral blood volume (nCBV90), and initial area under the time signal-intensity curve (IAUC90). The results of the areas under the receiver operating characteristic curve (AUCs) with cross-validation were compared between MGMT methylation and unmethylation groups.
RESULTS: MR imaging parameters demonstrated a trend toward higher accuracy in the MGMT promoter methylation group than in the unmethylation group (cross-validated AUCs = 0.70-0.95 and 0.56-0.87, respectively). The combination of MGMT methylation status with imaging parameters improved the AUCs from 0.70 to 0.75-0.90 for both readers in comparison with MGMT methylation status alone. The probability of pseudoprogression was highest (95.7 %) when nCBV90 was below 4.02 in the MGMT promoter methylation group.
CONCLUSIONS: MR imaging parameters could be stronger predictors of pseudoprogression in glioblastoma patients with the methylated MGMT promoter than in patients with the unmethylated MGMT promoter.
KEY POINTS: • The glioblastoma subgroup was stratified according to MGMT promoter methylation status. • Diagnostic values of diffusion and perfusion parameters for predicting pseudoprogression were compared. • Imaging parameters showed higher diagnostic accuracy in the MGMT promoter methylation group. • Imaging parameters were independent to MGMT promoter methylation status for predicting pseudoprogression. • Imaging biomarkers might demonstrate different diagnostic values according to MGMT promoter methylation.

Chaudhary AK, Chaudhary S, Ghosh K, et al.
Secretion and Expression of Matrix Metalloproteinase-2 and 9 from Bone Marrow Mononuclear Cells in Myelodysplastic Syndrome and Acute Myeloid Leukemia.
Asian Pac J Cancer Prev. 2016; 17(3):1519-29 [PubMed] Related Publications
BACKGROUND: Matrix metalloproteinase -2 (gelatinase-A, Mr 72,000 type IV collagenase, MMP-2) and -9 (gelatinase-B, Mr 92,000 type IV collagenase, MMP-9) are key molecules that play roles in tumor growth, invasion, tissue remodeling, metastasis and stem-cell regulation by digesting extracellular matrix barriers. MMP-2 and -9 are well known to impact on solid cancer susceptibility, whereas, in hematological malignancies, a paucity of data is available to resolve the function of these regulatory molecules in bone marrow mononuclear cells (BM-MNCs) and stromal cells of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
OBJECTIVES: The present study aimed to investigate mRNA expression and gelatinase A and B secretion from BM-MNCs in vitro and genotypic associations of MMP-2 (-1306 C/T; rs243865), MMP-9 (-1562 C/T; rs3918242), tissue inhibitor of metalloproteinase -1 (TIMP-1) (372T/C; rs4898, Exon 5) and TIMP-2 (-418G/C; rs8179090) in MDS and AML.
RESULTS: The study covered cases of confirmed MDS (n=50), AML (n=32) and healthy controls (n=110). MMP- 9 mRNA expression revealed 2 fold increased expression in MDS-RAEB II and 2.5 fold in AML M-4 (60-70% blasts). Secretion of gelatinase- B also revealed the MMP-9 mRNA expression and ELISA data also supported these data. We noted that those patients having more blast crises presented with more secretion of MMP-9 and its mRNA expression. In contrast MMP-9 (-1562 C/T) showed significant polymorphic associations in MDS (p<0.02) and AML (p<0.02). MMP-9 mRNA expression of C/T and T/T genotypes were 1.5 and 2.5 fold increased in MDS and AML respectively. In AML, MMP-2 C/T and T/T genotypes showed 2.0 fold mRNA expression. Only MMP-9 (-1306 C/T) showed significant 4 fold (p<0.001) increased risk with chemical and x-ray exposed MDS, while tobacco and cigarette smokers have 3 fold (p<0.04) risk in AML.
CONCLUSIONS: In view of our results, MMP-9 revealed synergistic secretion and expression in blast crises of MDS and AML with 'gene' polymorphic effects and is significantly associated with increased risk with tobacco, cigarette and environmental exposure. Release and secretion of these enzymes may influence hematopoietic cell behavior and may be important in the clinical point of view. It may offer valuable tools for diagnosis and prognosis, as well as possible targets for the treatments.

Town J, Pais H, Harrison S, et al.
Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target.
Proc Natl Acad Sci U S A. 2016; 113(13):3603-8 [PubMed] Free Access to Full Article Related Publications
The cell surface proteome of tumors mediates the interface between the transformed cells and the general microenvironment, including interactions with stromal cells in the tumor niche and immune cells such as T cells. In addition, the cell surface proteome of individual cancers defines biomarkers for that tumor type and potential proteins that can be the target of antibody-mediated therapy. We have used next-generation deep RNA sequencing (RNA-seq) coupled to an in-house database of genes encoding cell surface proteins (herein referred to as the surfaceome) as a tool to define a cell surface proteome of Ewing sarcoma compared with progenitor mesenchymal stem cells. This subtractive RNA-seq analysis revealed a specific surfaceome of Ewing and showed unexpectedly that the leucine-rich repeat and Ig domain protein 1 (LINGO1) is expressed in over 90% of Ewing sarcoma tumors, but not expressed in any other somatic tissue apart from the brain. We found that the LINGO1 protein acts as a gateway protein internalizing into the tumor cells when engaged by antibody and can carry antibody conjugated with drugs to kill Ewing sarcoma cells. Therefore, LINGO1 is a new, unique, and specific biomarker and drug target for the treatment of Ewing sarcoma.

Johnson N, De Ieso P, Migliorini G, et al.
Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer.
Cancer Res. 2016; 76(6):1485-93 [PubMed] Free Access to Full Article Related Publications
CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers.

Saunders EJ, Dadaev T, Leongamornlert DA, et al.
Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array.
Br J Cancer. 2016; 114(8):945-52 [PubMed] Related Publications
BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.
METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.
RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.
CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

Hu H, Arena F, Gianolio E, et al.
Mesoporous silica nanoparticles functionalized with fluorescent and MRI reporters for the visualization of murine tumors overexpressing αvβ3 receptors.
Nanoscale. 2016; 8(13):7094-104 [PubMed] Related Publications
A novel fluorescein/Gd-DOTAGA containing nanoprobe for the visualization of tumors by optical and Magnetic Resonance Imaging (MRI) is reported herein. It is based on the functionalization of the surface of small mesoporous silica nanoparticles (MSNs) (∼30 nm) with the arginine-glycine-aspartic (RGD) moieties, which are known to target αvβ3 integrin receptors overexpressed in several tumor cells. The obtained nanoprobe (Gd-MSNs-RGD) displays good stability, tolerability and high relaxivity (37.6 mM(-1) s(-1) at 21.5 MHz). After a preliminary evaluation of their cytotoxicity and targeting capability toward U87MG cells by in vitro fluorescence and MR imaging, the nanoprobes were tested in vivo by T1-weighted MR imaging of xenografted murine tumor models. The obtained results demonstrated that the Gd-MSNs-RGD nanoprobes are good reporters both in vitro and in vivo for the MR-visualization of tumor cells overexpressing αvβ3 integrin receptors.

Yang Y, Gong MF, Yang H, et al.
MR molecular imaging of tumours using ferritin heavy chain reporter gene expression mediated by the hTERT promoter.
Eur Radiol. 2016; 26(11):4089-4097 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: Using the human telomerase reverse transcriptase (hTERT) promoter and the modified ferritin heavy chain (Fth) reporter gene, reporter gene expression for MRI was examined in telomerase positive and negative tumour cells and xenografts.
METHODS: Activity of the reporter gene expression vector Lenti-hTERT-Fth1-3FLAG-Puro was compared to constitutive CMV-driven expression and to the untransfected parental control in five tumour cell lines: A549, SKOV3, 293T, U2OS and HPDLF. In vitro, transfected cells were evaluated for FLAG-tagged protein expression, iron accumulation and transverse relaxation. In vivo, tumours transduced by lentiviral vector injection were imaged using T2*WI. Changes in tumour signal intensity were validated by histology.
RESULTS: Only telomerase positive tumour cells expressed FLAG-tagged Fth and displayed an increase in R2* above the parental control, with a corresponding change in T2*WI. In addition, only telomerase positive tumours, transduced by injection of the reporter gene expression construct, exhibited a change in signal intensity on T2*WI. Tumour histology verified the expression of FLAG-tagged Fth and iron accumulation in telomerase positive tissue.
CONCLUSION: Reporter gene expression for MRI, using the Fth reporter and the hTERT promoter, may be a useful strategy for the non-invasive diagnosis of many types of cancer.
KEY POINTS: • Modified heavy chain of ferritin can serve as an MR reporter gene • hTERT promoter can direct the expression of reporter gene in cancer cells • MR reporter imaging mediated by hTERT promoter can be used for cancer diagnosis.

Bell RJ, Rube HT, Xavier-Magalhães A, et al.
Understanding TERT Promoter Mutations: A Common Path to Immortality.
Mol Cancer Res. 2016; 14(4):315-23 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Telomerase (TERT) activation is a fundamental step in tumorigenesis. By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven by oncogenes. The recently discovered, highly recurrent mutations in the promoter of TERT are found in over 50 cancer types, and are the most common mutation in many cancers. Transcriptional activation of TERT, via promoter mutation or other mechanisms, is the rate-limiting step in production of active telomerase. Although TERT is expressed in stem cells, it is naturally silenced upon differentiation. Thus, the presence of TERT promoter mutations may shed light on whether a particular tumor arose from a stem cell or more differentiated cell type. It is becoming clear that TERT mutations occur early during cellular transformation, and activate the TERT promoter by recruiting transcription factors that do not normally regulate TERT gene expression. This review highlights the fundamental and widespread role of TERT promoter mutations in tumorigenesis, including recent progress on their mechanism of transcriptional activation. These somatic promoter mutations, along with germline variation in the TERT locus also appear to have significant value as biomarkers of patient outcome. Understanding the precise molecular mechanism of TERT activation by promoter mutation and germline variation may inspire novel cancer cell-specific targeted therapies for a large number of cancer patients.

Ables GP, Hens JR, Nichenametla SN
Methionine restriction beyond life-span extension.
Ann N Y Acad Sci. 2016; 1363:68-79 [PubMed] Related Publications
Dietary methionine restriction (MR) extends life span across species via various intracellular regulatory mechanisms. In rodents, MR induces resistance against adiposity, improves hepatic glucose metabolism, preserves cardiac function, and reduces body size, all of which can affect the onset of age-related diseases. Recent studies have shown that MR-affected biomarkers, such as fibroblast growth factor 21, adiponectin, leptin, cystathionine β synthase, and insulin-like growth factor 1, can potentially alter physiology. The beneficial effects of MR could be explained in part by its ability to reduce mitochondrial oxidative stress. Studies have revealed that MR can reduce reactive oxygen species that damage cells and promote cancer progression. It has been demonstrated that either MR or the targeting of specific genes in the methionine cycle could induce cell apoptosis while decreasing proliferation in several cancer models. The complete mechanism underlying the actions of MR on the cell cycle during cancer has not been fully elucidated. Epigenetic mechanisms, such as methylation and noncoding RNAs, are also possible downstream effectors of MR; future studies should help to elucidate some of these mechanisms. Despite evidence that changes in dietary methionine can affect epigenetics, it remains unknown whether epigenetics is a mechanism in MR. This review summarizes research on MR and its involvement in metabolism, cancer, and epigenetics.

Ward ST, Weston CJ, Shepherd EL, et al.
Evaluation of serum and tissue levels of VAP-1 in colorectal cancer.
BMC Cancer. 2016; 16:154 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The endothelial adhesion molecule, vascular adhesion protein-1 (VAP-1, AOC3) promotes lymphocyte recruitment to tumours, although the contribution that VAP-1 makes to lymphocyte recruitment in human colorectal cancer (CRC) is unknown. VAP-1 exists in circulating soluble form (sVAP-1). A previous study demonstrated elevated sVAP-1 levels in CRC patients. The aim of this study was to confirm this finding and study the differences in tissue VAP-1 expression between CRC and healthy tissues.
METHODS: sVAP-1 levels were measured in the serum of 31 patients with CRC and 31 age- and sex-matched controls. Tissue VAP-1 levels were measured by immunohistochemistry, quantitative real-time PCR and Western blotting.
RESULTS: The mean sVAP-1 level ± SD was significantly lower in the CRC group compared with the control group (399 ± 138 ng/ml versus 510 ± 142 ng/ml, P = 0.003). Tissue VAP-1 protein and mRNA levels were significantly lower in CRC compared with normal colon tissue. VAP-1 immunostaining was practically absent from CRC.
CONCLUSIONS: VAP-1 is downregulated in human CRC and although the molecular basis of this down regulation is not yet known, we suggest it may be part of a mechanism used by the tumour to prevent the recruitment of anti-tumour immune cells. Our data contradicts the findings of others with regard sVAP-1 levels in patients with CRC. Possible reasons for this are discussed.

Ghigna MR, Dorfmuller P, Crutu A, et al.
Bronchial Paraganglioma with SDHB Deficiency.
Endocr Pathol. 2016; 27(4):332-337 [PubMed] Related Publications
Though most paragangliomas arise as sporadic tumors, the recent advantages in the genetic screening revealed that about 30 % of paragangliomas are linked to hereditary mutations, such as those involving SDH genes. A 22-year-old woman carrying a left main bronchus tumor underwent surgery in our institution. Her past medical history included a GIST without KIT or PDGFRA mutation. The histological examination revealed a nested proliferation of medium-sized cells expressing neuroendocrine markers (chromogranin A and synaptophysin). The neoplastic cells failed to express SDHB gene product. These findings led us to the final diagnosis of bronchial paraganglioma in the setting of Carney-Stratakis syndrome. Bronchial paragangliomas are exceedingly rare tumors with polymorphous clinical presentation, and usually benign clinical course. Though most paragangliomas are sporadic, some tumors are associated with specific hereditary disease, especially those occurring in young patients or in combination with other neoplasms.

Putman RK, Hatabu H, Araki T, et al.
Association Between Interstitial Lung Abnormalities and All-Cause Mortality.
JAMA. 2016; 315(7):672-81 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
IMPORTANCE: Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated.
OBJECTIVE: To investigate whether interstitial lung abnormalities are associated with increased mortality.
DESIGN, SETTING, AND POPULATION: Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006).
EXPOSURES: Interstitial lung abnormality status as determined by chest CT evaluation.
MAIN OUTCOMES AND MEASURES: All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.
RESULTS: Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis.
CONCLUSIONS AND RELEVANCE: In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.

Hoang B, Shi Y, Frost PJ, et al.
SGK Kinase Activity in Multiple Myeloma Cells Protects against ER Stress Apoptosis via a SEK-Dependent Mechanism.
Mol Cancer Res. 2016; 14(4):397-407 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: To assess the role of the serum and glucocorticoid-regulated kinase (SGK) kinase in multiple myeloma, we ectopically expressed wild type or a phosphomimetic version of SGK into multiple myeloma cell lines. These cells were specifically resistant to the ER stress inducers tunicamycin, thapsigargin, and bortezomib. In contrast, there was no alteration of sensitivity to dexamethasone, serum starvation, or mTORC inhibitors. Mining of genomic data from a public database indicated that low baseline SGK expression in multiple myeloma patients correlated with enhanced ability to undergo a complete response to subsequent bortezomib treatment and a longer time to progression and overall survival following treatment. SGK overexpressing multiple myeloma cells were also relatively resistant to bortezomib in a murine xenograft model. Parental/control multiple myeloma cells demonstrated a rapid upregulation of SGK expression and activity (phosphorylation of NDRG-1) during exposure to bortezomib and an SGK inhibitor significantly enhanced bortezomib-induced apoptosis in cell lines and primary multiple myeloma cells. In addition, a multiple myeloma cell line selected for bortezomib resistance demonstrated enhanced SGK expression and SGK activity. Mechanistically, SGK overexpression constrained an ER stress-induced JNK proapoptotic pathway and experiments with a SEK mutant supported the notion that SGK's protection against bortezomib was mediated via its phosphorylation of SEK (MAP2K4) which abated SEK/JNK signaling. These data support a role for SGK inhibitors in the clinical setting for myeloma patients receiving treatment with ER stress inducers like bortezomib.
IMPLICATIONS: Enhanced SGK expression and activity in multiple myeloma cells contributes to resistance to ER stress, including bortezomib challenge.

Stein RC, Dunn JA, Bartlett JM, et al.
OPTIMA prelim: a randomised feasibility study of personalised care in the treatment of women with early breast cancer.
Health Technol Assess. 2016; 20(10):xxiii-xxix, 1-201 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: There is uncertainty about the chemotherapy sensitivity of some oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers. Multiparameter assays that measure the expression of several tumour genes simultaneously have been developed to guide the use of adjuvant chemotherapy for this breast cancer subtype. The assays provide prognostic information and have been claimed to predict chemotherapy sensitivity. There is a dearth of prospective validation studies. The Optimal Personalised Treatment of early breast cancer usIng Multiparameter Analysis preliminary study (OPTIMA prelim) is the feasibility phase of a randomised controlled trial (RCT) designed to validate the use of multiparameter assay directed chemotherapy decisions in the NHS.
OBJECTIVES: OPTIMA prelim was designed to establish the acceptability to patients and clinicians of randomisation to test-driven treatment assignment compared with usual care and to select an assay for study in the main RCT.
DESIGN: Partially blinded RCT with adaptive design.
SETTING: Thirty-five UK hospitals.
PARTICIPANTS: Patients aged ≥ 40 years with surgically treated ER-positive HER2-negative primary breast cancer and with 1-9 involved axillary nodes, or, if node negative, a tumour at least 30 mm in diameter.
INTERVENTIONS: Randomisation between two treatment options. Option 1 was standard care consisting of chemotherapy followed by endocrine therapy. In option 2, an Oncotype DX(®) test (Genomic Health Inc., Redwood City, CA, USA) performed on the resected tumour was used to assign patients either to standard care [if 'recurrence score' (RS) was > 25] or to endocrine therapy alone (if RS was ≤ 25). Patients allocated chemotherapy were blind to their randomisation.
MAIN OUTCOME MEASURES: The pre-specified success criteria were recruitment of 300 patients in no longer than 2 years and, for the final 150 patients, (1) an acceptance rate of at least 40%; (2) recruitment taking no longer than 6 months; and (3) chemotherapy starting within 6 weeks of consent in at least 85% of patients.
RESULTS: Between September 2012 and 3 June 2014, 350 patients consented to join OPTIMA prelim and 313 were randomised; the final 150 patients were recruited in 6 months, of whom 92% assigned chemotherapy started treatment within 6 weeks. The acceptance rate for the 750 patients invited to participate was 47%. Twelve out of the 325 patients with data (3.7%, 95% confidence interval 1.7% to 5.8%) were deemed ineligible on central review of receptor status. Interviews with researchers and recordings of potential participant consultations made as part of the integral qualitative recruitment study provided insights into recruitment barriers and led to interventions designed to improve recruitment. Patient information was changed as the result of feedback from three patient focus groups. Additional multiparameter analysis was performed on 302 tumour samples. Although Oncotype DX, MammaPrint(®)/BluePrint(®) (Agendia Inc., Irvine, CA, USA), Prosigna(®) (NanoString Technologies Inc., Seattle, WA, USA), IHC4, IHC4 automated quantitative immunofluorescence (AQUA(®)) [NexCourse BreastTM (Genoptix Inc. Carlsbad, CA, USA)] and MammaTyper(®) (BioNTech Diagnostics GmbH, Mainz, Germany) categorised comparable numbers of tumours into low- or high-risk groups and/or equivalent molecular subtypes, there was only moderate agreement between tests at an individual tumour level (kappa ranges 0.33-0.60 and 0.39-0.55 for tests providing risks and subtypes, respectively). Health economics modelling showed the value of information to the NHS from further research into multiparameter testing is high irrespective of the test evaluated. Prosigna is currently the highest priority for further study.
CONCLUSIONS: OPTIMA prelim has achieved its aims of demonstrating that a large UK clinical trial of multiparameter assay-based selection of chemotherapy in hormone-sensitive early breast cancer is feasible. The economic analysis shows that a trial would be economically worthwhile for the NHS. Based on the outcome of the OPTIMA prelim, a large-scale RCT to evaluate the clinical effectiveness and cost-effectiveness of multiparameter assay-directed chemotherapy decisions in hormone-sensitive HER2-negative early breast would be appropriate to take place in the NHS.
TRIAL REGISTRATION: Current Controlled Trials ISRCTN42400492.
FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 10. See the NIHR Journals Library website for further project information. The Government of Ontario funded research at the Ontario Institute for Cancer Research. Robert C Stein received additional support from the NIHR University College London Hospitals Biomedical Research Centre.

Cheng C, Lou S, Andrews EH, et al.
Integrative Genomic Analyses Yield Cell-Cycle Regulatory Programs with Prognostic Value.
Mol Cancer Res. 2016; 14(4):332-43 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: Liposarcoma is the second most common form of sarcoma, which has been categorized into four molecular subtypes, which are associated with differential prognosis of patients. However, the transcriptional regulatory programs associated with distinct histologic and molecular subtypes of liposarcoma have not been investigated. This study uses integrative analyses to systematically define the transcriptional regulatory programs associated with liposarcoma. Likewise, computational methods are used to identify regulatory programs associated with different liposarcoma subtypes, as well as programs that are predictive of prognosis. Further analysis of curated gene sets was used to identify prognostic gene signatures. The integration of data from a variety of sources, including gene expression profiles, transcription factor-binding data from ChIP-Seq experiments, curated gene sets, and clinical information of patients, indicated discrete regulatory programs (e.g., controlled by E2F1 and E2F4), with significantly different regulatory activity in one or multiple subtypes of liposarcoma with respect to normal adipose tissue. These programs were also shown to be prognostic, wherein liposarcoma patients with higher E2F4 or E2F1 activity associated with unfavorable prognosis. A total of 259 gene sets were significantly associated with patient survival in liposarcoma, among which > 50% are involved in cell cycle and proliferation.
IMPLICATIONS: These integrative analyses provide a general framework that can be applied to investigate the mechanism and predict prognosis of different cancer types.

Phi JH, Choi JW, Seong MW, et al.
Association between moyamoya syndrome and the RNF213 c.14576G>A variant in patients with neurofibromatosis Type 1.
J Neurosurg Pediatr. 2016; 17(6):717-22 [PubMed] Related Publications
OBJECTIVE In a minority of patients with neurofibromatosis Type 1 (NF-1), cerebral vasculopathy reminiscent of moyamoya disease develops. This phenomenon is called moyamoya syndrome (MMS), but there are no known risk factors for the prediction of MMS in NF-1 patients. Polymorphism of the RNF213 gene has exhibited strong associations with familial and sporadic moyamoya disease and other cerebral vasculopathies. The aim of this study is to find whether the RNF213 c.14576G>A variant is associated with MMS development in the NF-1 population or not. METHODS The MMS group included 16 NF-1 patients with documented MMS. The control group consisted of 97 NF-1 patients without MMS. Genomic DNA samples were obtained from the saliva or blood of both groups, and the presence of the RNF213 c.14576G>A variant was assessed by Sanger sequencing. RESULTS In the MMS group, 3 patients had the RNF213 c.14576G>A variant (18.7%), whereas no patients with this genetic variation were observed in the control group (0%). There was a meaningful association between the RNF213 c.14576G>A variant and MMS development (p = 0.0024). The crude odds ratio was calculated as 50.57 (95% CI 1.57-1624.41). All 3 patients with MMS and the c.14576G>A variant were diagnosed with MMS at an early age and had bilateral involvement. CONCLUSIONS The RNF213 c.14576G>A variant is more common in NF-1 patients who develop MMS than in NF-1 patients without MMS. This variant might be a susceptibility gene for the NF-1-moyamoya connection.

Ghaleb AM, Elkarim EA, Bialkowska AB, Yang VW
KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis.
Mol Cancer Res. 2016; 14(4):385-96 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: The zinc finger transcription factor Krüppel-like factor 4 (KLF4) is frequently downregulated in colorectal cancer. Previous studies showed that KLF4 is a tumor suppressor in the intestinal tract and plays an important role in DNA damage-repair mechanisms. Here, the in vivo effects of Klf4 deletion were examined from the mouse intestinal epithelium (Klf4(ΔIS)) in a genetic or pharmacological setting of colonic tumorigenesis:Apc(Min/⁺) mutation or carcinogen treatment with azoxymethane (AOM), respectively.Klf4 (ΔIS)/Apc (Min/⁺) mice developed significantly more colonic adenomas with 100% penetrance as compared with Apc(Min/⁺) mice with intact Klf4 (Klf4(fl/fl)/Apc (Min/⁺)). The colonic epithelium of Klf4 (ΔIS)/Apc (Min/⁺)mice showed increased mTOR pathway activity, together with dysregulated epigenetic mechanism as indicated by altered expression of HDAC1 and p300. Colonic adenomas from both genotypes stained positive for γH2AX, indicating DNA double-strand breaks. InKlf4 (ΔIS)/Apc (Min/+) mice, this was associated with reduced nonhomologous end joining (NHEJ) repair and homologous recombination repair (HRR) mechanisms as indicated by reduced Ku70 and Rad51 staining, respectively. In a separate model, following treatment with AOM, Klf4 (ΔIS) mice developed significantly more colonic tumors than Klf4 (fl/fl) mice, with more Klf4 (ΔIS) mice harboring K-Rasmutations than Klf4 (fl/fl)mice. Compared with AOM-treated Klf4 (fl/fl)mice, adenomas of treated Klf4 (ΔIS) mice had suppressed NHEJ and HRR mechanisms, as indicated by reduced Ku70 and Rad51 staining. This study highlights the important role of KLF4 in suppressing the development of colonic neoplasia under different tumor-promoting conditions.
IMPLICATIONS: The study demonstrates that KLF4 plays a significant role in the pathogenesis of colorectal neoplasia.

Abuhaliema AM, Yousef AM, El-Madany NN, et al.
Influence of Genotype and Haplotype of MDR1 (C3435T, G2677A/T, C1236T) on the Incidence of Breast Cancer--a Case-Control Study in Jordan.
Asian Pac J Cancer Prev. 2016; 17(1):261-6 [PubMed] Related Publications
BACKGROUND: Breast cancer is the leading cause of cancer death among women and the second in humans worldwide. Many published studies have suggested an association between MDR1 polymorphisms and breast cancer risk. Our aim was to study the association between genetic polymorphism of MDR1 at three sites (C3435T, G2677A/T, and C1236T) and their haplotype and the risk of breast cancer in Jordanian females.
MATERIALS AND METHODS: A case-control study involving 150 breast cancer cases and 150 controls was conducted. Controls were age-matched to cases. The polymerase chain reaction/restriction fragment length polymorphism (PCR- RFLP) technique and sequencing were performed to analyse genotypes.
RESULTS: The distribution of MDR1 C3435T genotypes differed between cases and controls [cases, CC 45.3%, CT 41.3%, and TT 13.3%; controls, CC 13.4%, CT 43.3%, and TT 30.2%, p < 0.001]. Similarly, the distribution of G2677A/T significantly differed [cases, GG 43.1 %, GT+GA 50.9% and AA+TT 6%; controls, GG 29.6 %, GT+GA 50.9%, and AA+TT 19.4%, p = 0.004]. On the other hand, genotype and allelotype distribution of C1236T was not statistically different between cases and controls (p=0.56 and 0.26, respectively). The CGC haplotype increased the risk to breast cancer by 2.5-fold compared to others, while TGC and TTC haplotypes carried 2.5- and 5-fold lower risk of breast cancer, respectively.
CONCLUSIONS: Genetic polymorphisms of MDR1 C3435T and G2677A/T, but not C1236T, are associated with increased risk of breast cancer. In addition, CGC, TGC and TTC haplotypes have different impacts on the risk of breast cancer. Future, larger studies are needed to validate these findings.

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