CDKN2B

Gene Summary

Gene:CDKN2B; cyclin dependent kinase inhibitor 2B
Aliases: P15, MTS2, TP15, CDK4I, INK4B, p15INK4b
Location:9p21.3
Summary:This gene lies adjacent to the tumor suppressor gene CDKN2A in a region that is frequently mutated and deleted in a wide variety of tumors. This gene encodes a cyclin-dependent kinase inhibitor, which forms a complex with CDK4 or CDK6, and prevents the activation of the CDK kinases, thus the encoded protein functions as a cell growth regulator that controls cell cycle G1 progression. The expression of this gene was found to be dramatically induced by TGF beta, which suggested its role in the TGF beta induced growth inhibition. Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinase 4 inhibitor B
Source:NCBIAccessed: 31 August, 2019

Ontology:

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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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.

Tag cloud generated 31 August, 2019 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: CDKN2B (cancer-related)

Matsunaga N, Wakasaki T, Yasumatsu R, Kotake Y
Long Noncoding RNA,
Anticancer Res. 2019; 39(8):4073-4077 [PubMed] Related Publications
BACKGROUND/AIM: ANRIL is a long noncoding RNA located on INK4 locus, which encodes p15 and p16 that cause G
MATERIALS AND METHODS: Cells were transfected with siRNA oligonucleotides targeting ANRIL. Transfected cells were subjected to cell-cycle and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis.
RESULTS: Depletion of ANRIL increased p15 mRNA in FaDu cells, and p15 and p16 mRNA in CAL27 cells and inhibited proliferation of these cells. Cell cycle analysis showed that depletion of ANRIL caused arrest at the G
CONCLUSION: ANRIL promotes G

Zhang L, Wan Y, Jiang Y, et al.
Overexpression of BP1, an isoform of Homeobox Gene DLX4, promotes cell proliferation, migration and predicts poor prognosis in endometrial cancer.
Gene. 2019; 707:216-223 [PubMed] Related Publications
The expression of homeobox gene DLX4 has been verified in some tumors, but not in endometrial cancer. We found that expression of DLX7, a splicing isoform of DLX4, did not show any significant difference in expression between endometrial cancer and endometrium. However, BP1, another splicing isoform of DLX4, was highly expressed in endometrial cancer, and its expression was positively correlated with patient prognosis, cancer pathological grade, tumor invasion and metastasis. Lentiviral-mediated expression of BP1 in HEC-1-B cells accelerated the cell cycle progression from G0/G1 into S phase, and promoted cell proliferation and migration both in vitro and in vivo. Real-time PCR and western blotting showed that the expression levels of p15, p21 and E-cadherin significantly decreased, and levels of cyclinD1 and MMP-2 increased in endometrial cancer cells. In conclusion, our results demonstrate that high expression of BP1 is associated with poor prognosis in patients with endometrial cancer and promotes cell proliferation and migration.

Zhang H, Mao JS, Hu WF
Functional Genetic Single-Nucleotide Polymorphisms (SNPs) in Cyclin-Dependent Kinase Inhibitor 2A/B (CDKN2A/B) Locus Are Associated with Risk and Prognosis of Osteosarcoma in Chinese Populations.
Med Sci Monit. 2019; 25:1307-1313 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) encodes several tumor suppressor proteins. Aberrant genetic alterations in CDKN2A/B were found in some malignancies, which were believed to be associated with tumor originating and progression. We hypothesized that CDKN2A/B genetic polymorphisms might be associated with the risk of poorer prognosis of osteosarcoma in Chinese populations. MATERIAL AND METHODS We included 184 validated osteosarcoma cases and 185 cancer-free healthy controls in the study. Five single-nucleotide polymorphisms of CDKN2A/B (rs1063192, rs3218009, rs3217986, rs3217992, and rs3731257) were genotyped and underwent bioinformatic analysis. DNA from osteosarcoma individuals was isolated from frozen peripheral blood and DNA from healthy controls was extracted from fresh prepared peripheral blood. RESULTS An allele of the SNP rs3217992 is predictive for susceptibility to osteosarcoma, and it is associated with poorer prognosis of osteosarcoma. The GA and AA genotypes of rs3217992 are related to elevated risk of osteosarcoma. In addition, the GA and AA genotypes of rs3217992 in CDKN2A might indicate higher stage and increased risk of lung metastasis of osteosarcoma, resulting in worse prognosis. CONCLUSIONS Functional genetic polymorphisms in CDKN2A/B predict the susceptibility and outcome of osteosarcoma in Chinese individuals.

Jang W, Park J, Kwon A, et al.
CDKN2B downregulation and other genetic characteristics in T-acute lymphoblastic leukemia.
Exp Mol Med. 2019; 51(1):4 [PubMed] Free Access to Full Article Related Publications
We identified principal genetic alterations in 97.1% (99/102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order: NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B, CDKN2A, and genes on 9p21.3 in T-ALL (45.1%). Gene expression data demonstrated the downregulation of CDKN2B in most cases of T-ALL, whereas CDKN2A downregulation was mainly restricted to deletions. Additional quantitative methylation analysis demonstrated that CDKN2B downregulation stemmed from deletion and hypermethylation. Analysis of 64 patients with CDKN2B hypermethylation indicated an association with an older age of onset and early T cell precursor ALL, which involved very early arrest of T cell differentiation. Genes associated with methylation and myeloid neoplasms, including DNMT3A and NRAS, were more commonly mutated in T-ALL with CDKN2B hypermethylation. In particular, a CDKN2B biallelic deletion or high methylation level (≥45%), the age of onset, and the GATA3 and SH2B3 mutations were factors associated with a poor prognosis. This study clarifies that one of the most important genetic events in T-ALL, namely, CDKN2B downregulation, occurs mechanistically via deletion and hypermethylation. Different susceptible genetic backgrounds exist based on the CDKN2B downregulation mechanism.

Zhu B, Zhu Y, Tian J, et al.
A functional variant rs1537373 in 9p21.3 region is associated with pancreatic cancer risk.
Mol Carcinog. 2019; 58(5):760-766 [PubMed] Related Publications
9p21.3 has been identified as an unexpected hot point in multiple diseases GWAS including cancers, and we performed a two-stage case-control studies integrating functional assay strategy to find the potential functional variants modified susceptibility to pancreatic cancer (PC). An expanded Illumina HumanExome Beadchip of PC including 943 cases and 3908 controls was used to examine 39 tagSNPs in 9p21.3 and the promising single nucleotide polymorphism (SNP) was validated in stage 2 comprising 624 cases and 1048 controls. The strongest signal was rs6475609 (Odds ratio, OR = 0.81, 95% confidence interval, CI = 0.72-0.91) maps to the long non-coding RNA ANRIL. Bioinformatics analysis revealed rs1537373 lies in the linkage disequilibrium (LD) block which the rs6475609 tagged might have potential function and was also associated with a decreased risk of PC in both stages (OR = 0.82, 95% CI = 0.75-0.90 in combined analysis). Dual luciferase reporter assay and the electrophoretic mobility shift assay (EMSA) verified rs1537373 as the best candidate causative variant for influencing the activity of enhancer through differential binding to certain transcription factor. The expression quantitative trait loci (e-QTL) analysis indicated the genotypes of rs1537373 were associated with expression of CDKN2B gene (P dominant = 6.00 × 10

Qi M, Xiong X
Promoter hypermethylation of RARβ2, DAPK, hMLH1, p14, and p15 is associated with progression of breast cancer: A PRISMA-compliant meta-analysis.
Medicine (Baltimore). 2018; 97(51):e13666 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Numerous studies have investigated the associations between RARβ2, DAPK, hMLH1, p14, and p15 promoter hypermethylation and clinical progression of patients with breast cancer, however the results remained uncertain due to the small sample size. Therefore, we performed a meta-analysis to explore the role of RARβ2, DAPK, hMLH1, p14, and p15 promoter hypermethylation in the susceptibility and clinical progression of breast cancer.
METHODS: Eligible studies were obtained by searching Medicine, Embase, Web of knowledge, and Chinese National Knowledge Infrastructure (CNKI) databases. The odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations of RARβ2, DAPK, hMLH1, p14, and p15 promoter hypermethylation with breast cancer pathogenesis. Trial sequential analysis (TSA) was applied to observe the reliability of pooled results of RARβ2 gene, and obtain a conservative required information size (RIS).
RESULTS: In primary screened 445 articles, 39 literatures with 4492 breast cancer patients were finally enrolled in the final meta-analysis. The results indicated that the frequency of RARβ2 promoter hypermethylation in case group was significantly higher than the frequency of control group (OR = 7.21, 95% CI = 1.54-33.80, P < .05). The RARβ2 promoter hypermethylation had a significant association with lymph node metastasis of breast cancer (OR = 2.13, 95% CI = 1.04-4.47, P < .05). And, the RARβ2 promoter hypermethylation was more common in the breast cancer patients of TNM III-IV stage than those patients of TNM I-II stage (OR = 1.85, 95% CI = 1.33-2.57, P < .05). In addition, the promoter hypermethylation of DAPK, hMLH1, and p14 genes were significantly associated with the susceptibility of breast cancer (for DAPK, OR = 4.93, 95% CI = 3.17-7.65; for hMLH1, OR = 1.84, 95% CI = 1.26-1.29; for p14, OR = 22.52, 95% CI = 7.00-72.41; for p15, OR = 2.13, 95% CI = 0.30-15.07).
CONCLUSIONS: Our findings revealed that the RARβ2 promoter hypermethylation significantly increased the risk of breast cancer. In the meantime, the meta-analysis demonstrated that there were significant associations of RARβ2 promoter hypermethylation with lymph node metastasis and TNM-stage of breast cancer patients. In addition, DAPK, hMLH1, and p14 genes promoter hypermethylation were significantly associated with the susceptibility of breast cancer.

Frazão L, do Carmo Martins M, Nunes VM, et al.
BRAF V600E mutation and 9p21: CDKN2A/B and MTAP co-deletions - Markers in the clinical stratification of pediatric gliomas.
BMC Cancer. 2018; 18(1):1259 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genetic alterations in pediatric primary brain tumors can be used as diagnostic and prognostic markers and are the basis for the development of new target therapies that, ideally, would be associated with lower mortality and morbidity. This study evaluates the incidence and interplay of the presence of BRAF V600E mutation and chromosomal 9p21 deletions in a series of 100 pediatric gliomas, aiming to determine the role of these alterations in recurrence and malignant transformation, and to verify if they could be used in the clinical set for stratifying patients for tailored therapies and surveillance.
METHODS: Sanger sequencing was used for the assessment of BRAF mutations at exon 15 and Fluorescent In Situ Hybridization (FISH) with BAC: RP11-14192 for the detection of 9p21 alterations. Expression levels of the CDKN2A and MTAP by real-time PCR were evaluated in cases with 9p21 deletions. Statistical analysis of genetic and clinical data was performed using Graph Pad Prism 5 and SPSS Statistics 24 software.
RESULTS: In our cohort it was observed that 7 /78 (8,9%) of the low-grade tumors recurred and 2 (2,6%) showed malignant transformation. BRAF V600E mutations were detected in 15 cases. No statistically significant correlations were found between the presence of BRAF V600E mutation and patient's morphologic or clinical features. Deletions at 9p21 abrogating the CDKN2A/B and MTAP loci were rare in grade I gliomas (12.2%, p = 0.0178) but frequent in grade IV gliomas (62.5%, p = 0.0087). Moreover it was found that deletions at these loci were correlated with a shorter overall survival (p = 0.011) and a shorter progression-free survival (p = 0.016).
CONCLUSIONS: It was demonstrated that in these tumors BRAF V600E mutated and that CDKN2A/B MTAP co-deletions may be used for stratifying patients for a stricter surveillance. The Investigating and defining if glial tumors with CDKN2A/B and MTAP homozygous loss may be vulnerable to new forms of therapy, namely those affecting the methionine salvage pathway, was proven to be of importance.

Ezzidi I, Mtiraoui N, Mohmmed Ali ME, et al.
Impact of variants on type-2 diabetes risk genes identified through genomewide association studies in polycystic ovary syndrome: a case-control study.
J Genet. 2018; 97(5):1213-1223 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in females, and is associated with altered metabolic processes in particular insulin resistance and diabetes mellitus. PCOS shares with type-2 diabetes (T2D) a number of features, including beta cell dysfunction, impaired glucose tolerance and dyslipidaemia. Recently, genomewide association studies (GWAS) have reported a number of genes with reproducible associations and susceptibilities to T2D. To address this, we examined the association between the T2D GWAS candidate genes (

Neilsen BK, Sleightholm R, McComb R, et al.
Comprehensive genetic alteration profiling in primary and recurrent glioblastoma.
J Neurooncol. 2019; 142(1):111-118 [PubMed] Related Publications
INTRODUCTION: Glioblastoma (GBM) is heterogeneous and underlying genomic profiles influence evolution, resistance, and therapeutic responses. While extensive knowledge regarding genomic profiling of primary GBM exists, there remains a lack of understanding of genomic differences in recurrent GBM.
METHODS: We used the FoundationOne® comprehensive genomic profiling assay (CGP) to analyze ten matched primary and recurrent GBM. Genomic alterations (GA) were compared to the cancer database Catalogue of Somatic Mutations in Cancer (COSMIC).
RESULTS: All matched tumor pairs demonstrated differences in GA between the primary and recurrence including one resected without any intervening therapy. This suggests that time and/or therapeutic intervention contribute to GA. Although mutations were common to both the primary and recurrence, the percent reads varied substantially suggesting clonal expansions and contractions. For example, EGFR mutations were significantly expanded in three patients, and CNAs were increased in two patients at recurrence. Four genes that were commonly altered in both primary and recurrent GBM were more prevalent in our cohort than reported in COSMIC: CDKN2A (86% vs. 53%) and CDKN2B (86% vs. 54%) deletions, EGFR activating mutation (52% vs. 10%) or amplification (81% vs. 45%), and TERT mutation (95% vs. 51%). Lastly, PI3K pathway activating mutations were also commonly seen in our cohort (67%).
CONCLUSIONS: CGP revealed that GA identified in GBM changed over time and with treatment. Mutations in TERT, CDKN2A/CDKN2B, EGFR, and PI3K pathway were commonly observed in both primary and recurrent GBM revealing their prognostic and therapeutic potential. This may have important implications for individualized therapies and needs further evaluation.

Parada H, Cleveland RJ, North KE, et al.
Genetic polymorphisms of diabetes-related genes, their interaction with diabetes status, and breast cancer incidence and mortality: The Long Island Breast Cancer Study Project.
Mol Carcinog. 2019; 58(3):436-446 [PubMed] Free Access to Full Article Related Publications
To examine 143 diabetes risk single nucleotide polymorphisms (SNPs), identified from genome-wide association studies, in association with breast cancer (BC) incidence and subsequent mortality. A population-based sample of Caucasian women with first primary invasive BC (n = 817) and controls (n = 1021) were interviewed to assess diabetes status. Using the National Death Index, women with BC were followed for >18 years during which 340 deaths occurred (139 BC deaths). Genotyping was done using DNA extracted from blood samples. We used unconditional logistic regression to estimate age-adjusted odds ratios and 95% confidence intervals (CIs) for BC incidence, and Cox regression to estimate age-adjusted hazard ratios and CIs for all-cause and BC-specific mortality. Twelve SNPs were associated with BC risk in additive genotype models, at α = 0.05. The top three significant SNPs included SLC30A8-rs4876369 (P = 0.0034), HHEX-rs11187146 (P = 0.0086), and CDKN2A/CDKN2B-rs1333049 (P = 0.0094). Diabetes status modified the associations between rs4876369 and rs2241745 and BC incidence, on the multiplicative interaction scale. Six SNPs were associated with all-cause (CDKAL1-rs981042, P = 0.0032; HHEX-rs1111875, P = 0.0361; and INSR-rs919275, P = 0.0488) or BC-specific (CDKN2A/CDKN2B-rs3218020, P = 0.0225; CDKAL1-rs981042, P = 0.0246; and TCF2/HNF1B-rs3094508, P = 0.0344) mortality in additive genotype models, at α = 0.05. Genetic polymorphisms that increase the risk of developing diabetes may also increase the risk of developing and dying from BC.

Doğan Şiğva ZÖ, Balci Okcanoğlu T, Biray Avci Ç, et al.
Investigation of the synergistic effects of paclitaxel and herbal substances and endemic plant extracts on cell cycle and apoptosis signal pathways in prostate cancer cell lines.
Gene. 2019; 687:261-271 [PubMed] Related Publications
Paclitaxel, which isolated from Taxus brevifolia, is recently started to be used against prostate cancer treatment and it is a very effective compound against cancer. In this study, we aimed to test the synergistic effect of two plant active compounds (sulphoraphane (SFN) and silymarin (SILY)) and several endemic plant species from Turkey (such as Phlomis leucophracta, Rubia davisiana, Alkanna tinctoria), which are known to have anticarcinogenic effect on androgen-independent PC3 and DU145, and androgen-dependent VCaP prostate cancer cell lines, with paclitaxel on the expression of cell cycle signaling and apoptosis regulator genes. Herbal substances and endemic herbal extracts were combined with Paclitaxel drug. IC

Patil V, Mahalingam K
Comprehensive analysis of Reverse Phase Protein Array data reveals characteristic unique proteomic signatures for glioblastoma subtypes.
Gene. 2019; 685:85-95 [PubMed] Related Publications
The most common and lethal type of intracranial tumors include the astrocytomas. Grade IV astrocytoma or Glioblastoma (GBM) is highly aggressive and treatment-refractory with a median survival of only 14 to 16 months. Molecular profiling of GBMs reveals a high degree of intra- and inter-tumoral heterogeneity, and hence it is important to understand the important signalling axes that get deregulated in different GBM subtypes to provide effective tailor-made therapies. In this study, we have carried out extensive analysis of Reverse Phase Protein Array (RPPA) data from TCGA cohort to develop protein signatures that define glioma grades or subtypes. The protein signatures that distinguished Grade II or III from GBM had largely overlapped, and pathway analysis revealed the positive enrichment of extracellular matrix proteins (ECM), MYC pathway, uPAR pathway and G2/M checkpoint genes in GBM. We also identified protein signatures for GBMs with genetic alterations (IDH mutation, p53 mutation, EGFR amplification or mutation, CDKN2A/CDKN2B deletion, and PTEN mutation) that occur at high frequency. G-CIMP positive GBM-specific protein signature showed a large similarity with IDH1-mutant protein signature, thus signifying the importance of IDH1 mutation driving the G-CIMP. Gene expression subtype analysis revealed an association of specific proteins to classical (EGFR and phosphor variants), mesenchymal (SERPINE1, TAZ, and Myosin-IIa_pS1943), neural (TUBA1B), and proneural (GSK3_pS9) types. Univariate Cox regression analysis identified several proteins showing significant correlation with GBM survival. Multivariate analysis revealed that IGFBP2 and RICTOR_pT1135 are independent predictors of survival. Overall, our analyses reveal that specific proteins are regulated in different glioma subtypes underscoring the importance of diverse signalling axes playing important role in the pathogenesis of glioma tumors.

Yang Y, Peng XW
The silencing of long non-coding RNA ANRIL suppresses invasion, and promotes apoptosis of retinoblastoma cells through the ATM-E2F1 signaling pathway.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
As one of the most common primary intraocular carcinomas, retinoblastoma generally stems from the inactivation of the retinoblastoma

Lupicki K, Elifio-Esposito S, Fonseca AS, et al.
Patterns of copy number alterations in primary breast tumors of South African patients and their impact on functional cellular pathways.
Int J Oncol. 2018; 53(6):2745-2757 [PubMed] Related Publications
Breast cancer is the most common and the leading cause of female mortality among South African (SA) women. Several non‑biological and biological risk factors may be attributed to their observed high mortality rate; however, the molecular profiles associated with their breast tumors are poorly characterized. The present study examined the patterns of genome-wide copy number alterations (CNAs) and their potential impact on functional cellular pathways targeted by cancer driver genes in patients with breast cancer from the Western Cape region of SA. Array-comparative genomic hybridization analysis, performed in 28 cases of invasive breast cancer, revealed a mean number of 8.68±6.18 CNAs per case, affecting primarily the Xp22.3 and 6p21-p25 cytobands (57.14% of the cases), followed by 19p13.3-p13.11 (35.7%), 2p25.3-p24.3, 4p16.3-p15.3, 8q11.1-q24.3 and 16 p13.3-p11.2 (32.14%). Functional enrichment analysis of genes and microRNA targets mapped in these affected cytobands revealed critical cancer-associated pathways, including fatty acid biosynthesis and metabolism, extracellular matrix-receptor interaction, hippo and tumor protein p53 signaling pathways, which are regulated by known cancer genes, including CCND1, CDKN1A, MAPK1, MDM2, TP53 and SMAD2. An inverse correlation was observed among the number of CNAs and tumor size and grade; CNAs on the 4p and 6p cytobands were also inversely correlated with tumor grade. No association was observed in the number of CNAs and/or the affected cytobands and the different ethnic groups of the SA patients, indicating that their tumor genome is affected by CNAs, irrespectively of their genetic descent. Additional genomic tumor profiling in SA and other Sub-Saharan African patients with breast cancer is required to determine the associations of the CNAs observed with prognosis and clinical outcome.

Fanoni D, Corti L, Alberti-Violetti S, et al.
Array-based CGH of primary cutaneous CD8+ aggressive EPIDERMO-tropic cytotoxic T-cell lymphoma.
Genes Chromosomes Cancer. 2018; 57(12):622-629 [PubMed] Related Publications
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare provisionally categorized cutaneous lymphoma characterized by an aggressive course. Its pathogenesis and molecular mechanisms are still unknown, and only two individual cases have so far been molecularly characterized. The aim of this study was to define the pattern of numerical chromosomal alterations in tumor samples taken from 20 patients with pcAECyTCL at the time of diagnosis by means of array-comparative genomic hybridization (a-CGH). a-CGH detected numerous genomic aberrations in all the patients and, putting these together as a whole, they affected all the chromosomes. However, no specific profile of recurrent copy number alterations (CNAs) was found. Most of the gains involved regions previously described in other aggressive cutaneous lymphomas such as 7q, 8q24.3, and 17q, whereas the most significant CNA was the loss of 9p21.3 (CDKN2A-CDKN2B), which has already been found in a variety of malignant tumors and is associated with aggressive cutaneous T-cell lymphomas. In brief, CGH analysis revealed a large number of CNAs with only few recurring regions that probably do not represent driving events. The genomic instability found in this aggressive variant of cutaneous lymphoma may therefore be a secondary event but, at the time of the diagnosis of pcAECyTCL, the genomic integrity of tumor cells is already compromised.

Xu M, Chen X, Lin K, et al.
The long noncoding RNA SNHG1 regulates colorectal cancer cell growth through interactions with EZH2 and miR-154-5p.
Mol Cancer. 2018; 17(1):141 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mounting evidence demonstrates that long noncoding RNAs (lncRNAs) have critical roles during the initiation and progression of cancers. In this study, we report that the small nucleolar RNA host gene 1 (SNHG1) is involved in colorectal cancer progression.
METHODS: We analyzed RNA sequencing data to explore abnormally expressed lncRNAs in colorectal cancer. The effects of SNHG1 on colorectal cancer were investigated through in vitro and in vivo assays (i.e., CCK-8 assay, colony formation assay, flow cytometry assay, EdU assay, xenograft model, immunohistochemistry, and western blot). The mechanism of SNHG1 action was explored through bioinformatics, RNA fluorescence in situ hybridization, luciferase reporter assay, RNA pull-down assay, chromatin immunoprecipitation assay and RNA immunoprecipitation assay.
RESULTS: Our analysis revealed that SNHG1 was upregulated in human colorectal cancer tissues, and high SNHG1 expression was associated with reduced patient survival. We also found that high SNHG1 expression was partly induced by SP1. Moreover, SNHG1 knockdown significantly repressed colorectal cancer cells growth both in vitro and in vivo. Mechanistic investigations demonstrated that SNHG1 could directly interact with Polycomb Repressive Complex 2 (PRC2) and modulate the histone methylation of promoter of Kruppel like factor 2 (KLF2) and Cyclin dependent kinase inhibitor 2B (CDKN2B) in the nucleus. In the cytoplasm, SNHG1 acted as a sponge for miR-154-5p, reducing its ability to repress Cyclin D2 (CCND2) expression.
CONCLUSIONS: Taken together, the results of our studies illuminate how SNHG1 formed a regulatory network to confer an oncogenic function in colorectal cancer and suggest that SNHG1 may serve as a potential target for colorectal cancer diagnosis and treatment.

Bibi F, Ali I, Naseer MI, et al.
Detection of genetic alterations in gastric cancer patients from Saudi Arabia using comparative genomic hybridization (CGH).
PLoS One. 2018; 13(9):e0202576 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The present study was conducted to discover genetic imbalances such as DNA copy number variations (CNVs) associated with gastric cancer (GC) and to examine their association with different genes involved in the process of gastric carcinogenesis in Saudi population.
METHODS: Formalin-fixed paraffin-embedded (FFPE) tissues samples from 33 gastric cancer patients and 15 normal gastric samples were collected. Early and late stages GC samples were genotyped and CNVs were assessed by using Illumina HumanOmni1-Quad v.1.0 BeadChip.
RESULTS: Copy number gains were more frequent than losses throughout all GC samples compared to normal tissue samples. The mean number of the altered chromosome per case was 64 for gains and 40 for losses, and the median aberration length was 679115bp for gains and 375889bp for losses. We identified 7 high copy gain, 52 gains, 14 losses, 32 homozygous losses, and 10 copy neutral LOHs (loss of heterozygosities). Copy number gains were frequently detected at 1p36.32, 1q12, 1q22, 2p11.1, 4q23-q25, 5p12-p11, 6p21.33, 9q12-q21.11, 12q11-q12, 14q32.33, 16p13.3, 17p13.1, 17q25.3, 19q13.32, and losses at 1p36.23, 1p36.32, 1p32.1, 1q44, 3q25.2, 6p22.1, 6p21.33, 8p11.22, 10q22.1, 12p11.22, 14q32.12 and 16q24.2. We also identified 2 monosomy at chromosome 14 and 22, 52 partially trisomy and 22 whole chromosome 4 neutral loss of heterozygosities at 13q14.2-q21.33, 5p15.2-p15.1, 5q11.2-q13.2, 5q33.1-q34 and 3p14.2-q13.12. Furthermore, 11 gains and 2 losses at 1p36.32 were detected for 11 different GC samples and this region has not been reported before in other populations. Statistical analysis confirms significant association of H. pylori infection with T4 stage of GC as compare to control and other stages.
CONCLUSIONS: We found that high frequency of copy number gains and losses at 1p36.23, 1p32.1, 1p36.32, 3q25.2, 6p21.33 and 16q24.2 may be common events in gastric cancer. While novel CNVs at 1p36.32 harbouring PRDM16, TP73 and TP73-AS1 genes showed 11 gains and 2 losses for 11 different GC cases and this region is not reported yet in Database of Genomic Variants may be specific to Saudi population.

Chen X, Liu C, Zhao R, et al.
Synergetic and Antagonistic Molecular Effects Mediated by the Feedback Loop of p53 and JNK between Saikosaponin D and SP600125 on Lung Cancer A549 Cells.
Mol Pharm. 2018; 15(11):4974-4984 [PubMed] Related Publications
We jointly analyzed the changes in cell cycle arrest and distribution, the accumulation of subphase cells, apoptosis, and proliferation in A549 cells treated with Saikosaponin D (Ssd) and JNK inhibitor SP600125 alone or in combination. Our results indicated that cell cycle arrest at G0/G1, S, and G2/M phases was coupled with the accumulation of subG1, subS, and subG2 cells, corresponding to early apoptosis, DNA endoreplication, and later inhibitory proliferation, respectively. Analyzing the expression of 18 cell cycle regulatory genes and JNK and phosphorylated JNK (pJNK) levels revealed an enhancement in these factors by Ssd. Additional SP600125 weakened or eliminated the Ssd-induced increase of these factors except that p53/p21 and Rassfia levels were further improved. Ingenuity Pathway Analysis (IPA) of the interactions of these factors revealed a negative synergistic effect on apoptosis while a positive synergistic effect on proliferative inhibition of the two drugs: (1) Ssd induced apoptosis via the activation of two axes, TGFα-JNK-p53 and TGFα-Rassfia-Mst1. By eliminating the Ssd-induced increase of JNK/pJNK, additional SP600125 weakened the Ssd-induced apoptotic axis of TGFα-JNK-p53 and simultaneously abolished Ssd-induced apoptosis; (2) Ssd inhibited proliferation by the activation of two axes, TGFβ-p53/p21/p27/p15/p16 and TGFα-Rassfia-cyclin D1. By improving the Ssd-induced increase of p53/p21 and Rassfia, additional SP600125 enhanced the two axes of Ssd-induced inhibitory proliferation. Analyzing JNK/pJNK, p53, phospho-p53, and TNF-α levels revealed an opposite association of JNK/pJNK with p53 while consistent with phospho-p53 and TNF-α, which supported the proposals that JNK/pJNK negatively regulated p53 level, while it mediated p53 phosphorylation to transcriptionally activate TNF-α expression of apoptotic gene and trigger apoptosis. With the multiple roles, JNK/pJNK forms a synergetic and antagonistic feedback loop with phospho-p53/p53. Within the feedback loop, (1) Ssd-induced apoptosis depended on JNK/pJNK activities mediating phospho-p53 that activated TNF-α expression; (2) by weakening the negative regulation of JNK/pJNK in p53, SP600125 enhanced p53 level and the Ssd-induced inhibitory proliferation axes of TGFβ-p53/p21/p27/p15/p16. The results indicated the central coordinating roles of the feedback loop in the synergistic and antagonistic effects of the two drugs in A549 cells and provided a rationale for the combination of Ssd with SP600125 in the treatment of lung cancer.

Zhu Z, Zhao L, Brittingham A, et al.
Anticancer Res. 2018; 38(9):5079-5086 [PubMed] Related Publications
BACKGROUND/AIM: Cervical cancer is one of the deadliest gynecological cancers in USA. The role of Trichomonas Vaginalis (T. Vag) in the etiology or pathogenesis of cervical cancer is still poorly understood and controversial.
MATERIALS AND METHODS: Clonogenic assay, PCNA staining, TUNEL staining and caspase-3 activity assay were used to investigate the direct in vitro effect of T. Vag on human cervical cancer by using HeLa cells. We further investigated the potential molecular mechanisms using RT-PCR and immunohistochemical staining.
RESULTS: We found that culture supernatant of T. Vag inhibited growth of HeLa cervical cancer cells and this correlated with up-regulation of p15. We also found that culture supernatant of T. Vag induced apoptosis of HeLa cells and this correlated with up-regulation of Fas, TRAIL and TRAILR1.
CONCLUSION: Culture supernatant of T. Vag inhibits growth of HeLa cervical cancer cells by inhibition of proliferation and promotion of apoptosis. Our study might be helpful to address the association between the development of cervical cancer and infection of T. Vag.

Lopes-Ventura S, Pojo M, Matias AT, et al.
The efficacy of HRAS and CDK4/6 inhibitors in anaplastic thyroid cancer cell lines.
J Endocrinol Invest. 2019; 42(5):527-540 [PubMed] Related Publications
PURPOSE: Anaplastic thyroid carcinomas (ATCs) are non-responsive to multimodal therapy, representing one of the major challenges in thyroid cancer. Previously, our group has shown that genes involved in cell cycle are deregulated in ATCs, and the most common mutations in these tumours occurred in cell proliferation and cell cycle related genes, namely TP53, RAS, CDKN2A and CDKN2B, making these genes potential targets for ATCs treatment. Here, we investigated the inhibition of HRAS by tipifarnib (TIP) and cyclin D-cyclin-dependent kinase 4/6 (CDK4/6) by palbociclib (PD), in ATC cells.
METHODS: ATC cell lines, mutated or wild type for HRAS, CDKN2A and CDKN2B genes, were used and the cytotoxic effects of PD and TIP in each cell line were evaluated. Half maximal inhibitory concentration (IC50) values were determined for these drugs and its effects on cell cycle, cell death and cell proliferation were subsequently analysed.
RESULTS: Cell culture studies demonstrated that 0.1 µM TIP induced cell cycle arrest in the G2/M phase (50%, p < 0.01), cell death, and inhibition of cell viability (p < 0.001), only in the HRAS mutated cell line. PD lowest concentration (0.1 µM) increased significantly cell cycle arrest in the G0/G1 phase (80%, p < 0.05), but only in ATC cell lines with alterations in CDKN2A/CDKN2B genes; additionally, 0.5 µM PD induced cell death. The inhibition of cell viability by PD was more pronounced in cells with alterations in CDKN2A/CDKN2B genes (p < 0.05) and/or cyclin D1 overexpression.
CONCLUSIONS: This study suggests that TIP and PD, which are currently in clinical trials for other types of cancer, may play a relevant role in ATC treatment, depending on the specific tumour molecular profile.

Gao S, Zhou B, Li H, et al.
Long noncoding RNA HOTAIR promotes the self-renewal of leukemia stem cells through epigenetic silencing of p15.
Exp Hematol. 2018; 67:32-40.e3 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic disorder initiated from a small subset of leukemia stem cell (LSC), which presents unrestricted self-renewal and proliferation. Long non-coding RNA HOTAIR is abundantly expressed and plays oncogenic roles in solid cancer and AML. However, whether HOTAIR regulates the self-renewal of LSC is largely unknown. Here, we reported that the expression of HOTAIR was increased in LSC than in normal hematological stem and progenitor cells (HSPCs). HOTAIR inhibition by short hairpin RNAs (shRNAs) decreased colony formation in leukemia cell lines and primary AML blasts. We then investigated the role of HOTAIR in leukemia in vivo. HOTAIR knockdown extends the survival time in U937-transplanted NSG mice. Furthermore, HOTAIR knockdown reduced infiltration of leukemic blasts, decreased frequency of LSC, and prolonged overall survival in MLL-AF9-induced murine leukemia, suggesting that HOTAIR is required for the maintenance of AML. Mechanistically, HOTAIR inhibited p15 expression through zeste homolog 2 (EZH2)-enrolled tri-methylation of Lys 27 of histone H3 (H3K27me3) in p15 promoter. In addition, p15 partially reversed the decrease of colony and proliferation induced by HOTAIR knockdown, suggesting that p15 plays an important role in the leukemogenesis by HOTAIR. In conclusion, our study suggests that HOTAIR facilitates leukemogenesis by enhancing self-renewal of LSC. HOTAIR might be a potential target for anti-LSC therapy.

Zheng Q, Fan H, Meng Z, et al.
Histone demethylase KDM2B promotes triple negative breast cancer proliferation by suppressing p15INK4B, p16INK4A, and p57KIP2 transcription.
Acta Biochim Biophys Sin (Shanghai). 2018; 50(9):897-904 [PubMed] Related Publications
H3K4me3 and H3K36me2 histone demethylase KDM2B is an epigenetic regulatory factor involved in cell proliferation in numerous cells including breast cancer cells, however, the regulatory mechanism of KDM2B in cell proliferation of breast cancer cells, specifically in triple negative breast cancer (TNBC), remains largely unknown. In this study, we showed that higher expression level of KDM2B was associated with poor prognosis in TNBC. Using cell proliferation assay, we found that KDM2B promoted TNBC cell proliferation by suppressing the transcription of the cell cycle inhibitors p15INK4B, p16INK4A, and p57KIP2. Chromatin immunoprecipitation assay results showed that KDM2B bound to the promoters of these genes and thereby reduced the H3K4me3 and H3K36me2 levels, leading to the suppression of gene transcription in a histone demethylation activity-dependent manner. Silencing of p15INK4B, p16INK4A, and p57KIP2 in TNBC cells was shown to restore the promoting effect of KDM2B on TNBC cell proliferation. The present study reveals a novel cell regulatory mechanism through which KDM2B promotes TNBC cell proliferation by binding to the promoters of p15INK4B, p16INK4A, and p57KIP2, which reduces H3K4me3 and H3K36me2 levels to suppress gene transcription.

Wang X, He M, Li J, et al.
KLF15 suppresses cell growth and predicts prognosis in lung adenocarcinoma.
Biomed Pharmacother. 2018; 106:672-677 [PubMed] Related Publications
Krüppel-like factors (KLFs) are transcription factors containing three different C2H2-type zinc finger domains in their carboxy-terminal regions which have been identified to play important roles in a variety of cancers. However, little is known about KLF15 in lung adenocarcinoma (LAUD). Our study demonstrated that the expression levels of KLF15 were observably down-regulated in LAUD tissues compared to paired adjacent normal tissues. LUAD patients with low expression levels of KLF15 have worse prognosis than those with high expression levels of KLF15. KLF15 could suppress cell growth, which was partly via up-regulating CDKN1 A/p21 and CDKN2A/p15. Our findings suggested that KLF15 showed a significant role in LAUD progression and may shed light on a promising novel therapeutic target for blocking progression of LAUD.

Pellatt AJ, Mullany LE, Herrick JS, et al.
The TGFβ-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs.
J Transl Med. 2018; 16(1):191 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The TGFβ-signaling pathway plays an important role in the pathogenesis of colorectal cancer (CRC). Loss of function of several genes within this pathway, such as bone morphogenetic proteins (BMPs) have been seen as key events in CRC progression.
METHODS: In this study we comprehensively evaluate differential gene expression (RNASeq) of 81 genes in the TGFβ-signaling pathway and evaluate how dysregulated genes are associated with miRNA expression (Agilent Human miRNA Microarray V19.0). We utilize paired carcinoma and normal tissue from 217 CRC cases. We evaluate the associations between differentially expressed genes and miRNAs and sex, age, disease stage, and survival months.
RESULTS: Thirteen genes were significantly downregulated and 14 were significantly upregulated after considering fold change (FC) of > 1.50 or < 0.67 and multiple comparison adjustment. Bone morphogenetic protein genes BMP5, BMP6, and BMP2 and growth differentiation factor GDF7 were downregulated. BMP4, BMP7, INHBA (Inhibin beta A), TGFBR1, TGFB2, TGIF1, TGIF2, and TFDP1 were upregulated. In general, genes with the greatest dysregulation, such as BMP5 (FC 0.17, BMP6 (FC 0.25), BMP2 (FC 0.32), CDKN2B (FC 0.32), MYC (FC 3.70), BMP7 (FC 4.17), and INHBA (FC 9.34) showed dysregulation in the majority of the population (84.3, 77.4, 81.1, 80.2, 82.0, 51.2, and 75.1% respectively). Four genes, TGFBR2, ID4, ID1, and PITX2, were un-associated or slightly upregulated in microsatellite-stable (MSS) tumors while downregulated in microsatellite-unstable (MSI) tumors. Eight dysregulated genes were associated with miRNA differential expression. E2F5 and THBS1 were associated with one or two miRNAs; RBL1, TGFBR1, TGIF2, and INHBA were associated with seven or more miRNAs with multiple seed-region matches. Evaluation of the joint effects of mRNA:miRNA identified interactions that were stronger in more advanced disease stages and varied by survival months.
CONCLUSION: These data support an interaction between miRNAs and genes in the TGFβ-signaling pathway in association with CRC risk. These interactions are associated with unique clinical characteristics that may provide targets for further investigations.

Riess JW, Gandara DR, Frampton GM, et al.
Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC.
J Thorac Oncol. 2018; 13(10):1560-1568 [PubMed] Related Publications
INTRODUCTION: EGFR exon 20 insertions (EGFRex20ins) comprise an uncommon subset of EGFR-activating alterations relatively insensitive to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). However, recent early clinical data suggests these patients may benefit from newer-generation EGFR-TKIs. Comprehensive genomic profiling (CGP) identifies a broad spectrum of EGFRex20ins and associated co-occurring genomic alterations (GAs) present in NSCLC.
METHODS: Hybrid capture-based CGP was performed prospectively on 14,483 clinically annotated consecutive NSCLC specimens to a mean coverage depth of greater than 650X for 236 or 315 cancer-related genes.
RESULTS: Of 14,483 NSCLC cases, CGP identified 263 (1.8%) cases with EGFRex20ins, representing 12% (263 of 2251) of cases with EGFR mutations. Sixty-four unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%). EGFR amplification occurred in 22% (57 of 263). The most common co-occurring GAs effected tumor protein p53 (TP53) (56%), cyclin dependent kinase inhibitor 2A (CDKN2A) (22%), cyclin dependent kinase inhibitor 2B (CDKN2B) (16%), NK2 homeobox 1 (NKX2-1) (14%) and RB transcriptional corepressor 1 (RB1) (11%); co-occurring GAs in other known lung cancer drivers were rare (5%). Average tumor mutational burden was low (mean 4.3, range 0 to 40.3 mutations/Mb). Clinical outcomes to first- and second-generation EGFR TKIs were obtained for five patients and none responded.
CONCLUSIONS: In the largest series of EGFRex20ins NSCLC, diverse EGFRex20ins were detected in 12% of EGFR-mutant NSCLC, a higher frequency than previously reported in smaller single-institution studies. Clinical outcomes showed lack of response to EGFR TKIs. Tumor mutational burden was low, consistent with non-smoking associated NSCLC. Comprehensive sequencing revealed increased proportion and wide variety of EGFRex20ins, representing a population of patients significant enough for focused efforts on effective interventions.

Lu X, Zhang Q, Wang Y, et al.
Molecular classification and subtype-specific characterization of skin cutaneous melanoma by aggregating multiple genomic platform data.
J Cancer Res Clin Oncol. 2018; 144(9):1635-1647 [PubMed] Related Publications
PURPOSE: Traditional classification of melanoma is widely utilized with little apparent results making the development of robust classifiers that can guide therapies an urgency. Successful seminal research on classification has provided a wider understanding of cancer from multiple molecular profiles, respectively. However, it may ignore the complementary nature of the information provided by different types of data, which motivated us to subtype melanoma by aggregating multiple genomic platform data.
METHODS: Aggregating three omics data of 328 melanoma samples, melanoma subtyping was performed by three clustering methods. Differences across subtypes were extracted by functional enrichment, epigenetically silencing, gene mutations and clinical features. Subtypes were further distinguished by putative biomarkers.
RESULTS: Functional enrichment of the subtype-specific differential expression genes endowed subtypes new designation: immune, melanin and ion, in which the first subtype was enriched for immune system, the second was characterized by melanin and pigmentation, and the third was enriched for ion-involved transmission process. Subtypes also differed in age, Breslow thickness, tumor site, mutation frequency of BRAF, PTGS2, CDKN2A, CDKN2B and incidence of epigenetically silencing for IL15RA, EPSTI1, LXN, CDKN1B genes.
CONCLUSIONS: Skin cutaneous melanoma can be robustly divided into three subtypes by SNFCC

Qin Y, Zhou X, Huang C, et al.
Lower miR-340 expression predicts poor prognosis of non-small cell lung cancer and promotes cell proliferation by targeting CDK4.
Gene. 2018; 675:278-284 [PubMed] Related Publications
Aberrantly microRNAs (miRs) expression is reported to be involved in tumorigenesis and development in non-small cell lung cancer (NSCLC). MiR-340 had been identified to be downregulated in NSCLC in the previous study. However, the underlying mechanisms of miR-340 involved in NSCLC progression still needed to be well known. In the present study, we confirmed that miR-340 expression was notably down-regulated in NSCLC tissues compared to matched adjacent noncancerous lung tissues by quantitative real time PCR (qRT-PCR) analyses. Lower miR-340 expression positively related to lymph node metastasis, larger tumor size, advanced TNM stage and poor prognosis of NSCLC patients. In vitro assays, we demonstrated that upregulation of miR-340 expression suppressed cell proliferation ability. Bioinformatics analysis and luciferase reporter assays revealed that miR-340 directly targeted the 3'-untranslated (3'UTR) region of CDK4 mRNA. Over-expression of miR-340 suppressed cell proliferation by regulating CDK4 expression in NSCLC cells. Additionally, we showed that increased miR-340 expression promoted the expression of cell proliferation related protein CDK6 expression, but decreasing the P15 and P21 expression. In vivo, we verified that miR-340 overexpression also inhibited tumor growth by regulating CDK4 expression. Therefore, these findings revealed miR-340 functions as a tumor suppressor in NSCLC cells and may provide a potential target of NSCLC treatment.

Rahmani M, Talebi M, Hagh MF, et al.
Aberrant DNA methylation of key genes and Acute Lymphoblastic Leukemia.
Biomed Pharmacother. 2018; 97:1493-1500 [PubMed] Related Publications
DNA methylation is a dynamic process influencing gene expression by altering either coding or non-coding loci. Despite advances in treatment of Acute Lymphoblastic Leukemia (ALL); relapse occurs in approximately 20% of patients. Nowadays, epigenetic factors are considered as one of the most effective mechanisms in pathogenesis of malignancies. These factors are reversible elements which can be potentially regarded as therapy targets and disease prognosis. DNA methylation, which primarily serves as transcriptional suppressor, mostly occurs in CpG islands of the gene promoter regions. This was shown as a key epigenetic factor in inactivating various tumor suppressor genes during cancer initiation and progression. We aimed to review methylation status of key genes involved in hematopoietic malignancies such as IKZF1, CDKN2B, TET2, CYP1B1, SALL4, DLC1, DLX family, TP73, PTPN6, and CDKN1C; and their significance in pathogenesis of ALL. The DNA methylation alterations in promoter regions of the genes have been shown to play crucial roles in tumorigenesis. Methylation -based inactivation of these genes has also been reported as associated with prognosis in acute leukemia. In this review, we also addressed the association of gene expression and methylation pattern in ALL patients.

Tomoyasu C, Imamura T, Tomii T, et al.
Copy number abnormality of acute lymphoblastic leukemia cell lines based on their genetic subtypes.
Int J Hematol. 2018; 108(3):312-318 [PubMed] Related Publications
In this study, we performed genetic analysis of 83 B cell precursor acute lymphoblastic leukemia (B-ALL) cell lines. First, we performed multiplex ligation-dependent probe amplification analysis to identify copy number abnormalities (CNAs) in eight genes associated with B-ALL according to genetic subtype. In Ph

Yu LB, Tu YT, Huang JW, et al.
Hypermethylation of CpG islands is associated with increasing chromosomal damage in chinese lead-exposed workers.
Environ Mol Mutagen. 2018; 59(6):549-556 [PubMed] Related Publications
Lead is a widely existing environmental pollutant with potential carcinogenicity. To investigate the association of blood lead level (B-Pb) with potential chromosomal damage and cancer, we analyzed micronucleus (MN) frequency of peripheral blood lymphocytes (PBLs) and the methylation status of six human tumor suppressor genes (TSGs) post lead exposure. In the study, 147 lead-exposed workers were divided into two groups according to their B-Pb P

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