Gene Summary

Gene:EEF1E1; eukaryotic translation elongation factor 1 epsilon 1
Aliases: P18, AIMP3
Summary:This gene encodes a multifunctional protein that localizes to both the cytoplasm and nucleus. In the cytoplasm, the encoded protein is an auxiliary component of the macromolecular aminoacyl-tRNA synthase complex. However, its mouse homolog has been shown to translocate to the nucleus in response to DNA damage, and it plays a positive role in ATM/ATR-mediated p53 activation. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring downstream MUTED (muted homolog) gene. An EEF1E1-related pseudogene has been identified on chromosome 2. [provided by RefSeq, Dec 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:eukaryotic translation elongation factor 1 epsilon-1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • FUBP1
  • Ubiquitin-Protein Ligases
  • Long Noncoding RNA
  • Knockout Mice
  • Single-Stranded Conformational Polymorphism
  • Bladder Cancer
  • Tumor Suppressor Gene
  • EEF1A2
  • Xenograft Models
  • Peptide Elongation Factors
  • DNA Helicases
  • p38 Mitogen-Activated Protein Kinases
  • Carcinogenesis
  • Cystectomy
  • Cultured Cells
  • Mice, Inbred BALB C
  • Tumor Suppressor Proteins
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-myc
  • Ubiquitination
  • Neoplasm Invasiveness
  • Ubiquitin
  • TP53
  • DNA-Binding Proteins
  • Biological Models
  • Embryo, Mammalian
  • Transcriptome
  • EEF1D protein, human
  • Databases, Nucleic Acid
  • Peptide Chain Elongation, Translational
  • Tissue Array Analysis
  • Lung Cancer
  • Fibroblasts
  • HeLa Cells
  • Cancer Gene Expression Regulation
  • EEF1A1
  • EEF1E1
  • Chromosome 6
  • Western Blotting
  • Cancer DNA
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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: EEF1E1 (cancer-related)

Jiao Y, Feng Y, Wang X
Regulation of Tumor Suppressor Gene CDKN2A and Encoded p16-INK4a Protein by Covalent Modifications.
Biochemistry (Mosc). 2018; 83(11):1289-1298 [PubMed] Related Publications
CDKN2A is one of the most studied tumor suppressor genes. It encodes the p16-INK4a protein that plays a critical role in the cell cycle progression, differentiation, senescence, and apoptosis. Mutations in CDKN2A or dysregulation of its functional activity are frequently associated with various types of human cancer. As a cyclin-dependent kinase inhibitor, p16-INK4a forms a complex with cyclin-dependent kinases 4/6 (CDK4/6) thereby competing with cyclin D. It is believed that the helix-turn-helix structures in the content of tandem ankyrin repeats in p16-INK4a are required for the protein interaction with CDK4. Until recently, the mechanisms considered to be involved in the regulation of p16-INK4a functions and cancer development have been mutations in DNA, homozygous or heterozygous gene loss, and methylation of CDKN2A promoter region. In this review, we discuss recent findings on the regulation of p16-INK4a by covalent modifications at both transcriptional and post-translational levels.

Sarun KH, Lee K, Williams M, et al.
Genomic Deletion of
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of

Kahn SA, Wang X, Nitta RT, et al.
Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma.
Nat Commun. 2018; 9(1):4121 [PubMed] Free Access to Full Article Related Publications
Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway.

Hsu CL, Lui KW, Chi LM, et al.
Integrated genomic analyses in PDX model reveal a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for nasopharyngeal carcinoma.
J Exp Clin Cancer Res. 2018; 37(1):233 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets.
METHODS: We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs.
RESULTS: A relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in > 90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients' plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer.
CONCLUSIONS: Our integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.

Owusu-Afriyie O, Owiredu WKBA, Owusu-Danquah K, et al.
Expression of immunohistochemical markers in non-oropharyngeal head and neck squamous cell carcinoma in Ghana.
PLoS One. 2018; 13(8):e0202790 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Head and neck cancers include carcinomas of the oral cavity, larynx, sinonasal tract and nasopharynx. Studies on molecular expression of prognostic tumour markers in Ghana are scarce. The purpose of this study was to determine the expression of p53, p16, EGFR, Cyclin-D1 and HER2 among patients with non-oropharyngeal head and neck squamous cell carcinoma (HNSCC).
METHODOLOGY: Tissue microarrays from 154 histologically confirmed non-oropharyngeal HNSCC at the Komfo Anokye Teaching Hospital from 2006-2014 were constructed using duplicate cores of representative and viable areas from tumours. Expression of EGFR, p53, p16, Cyclin-D1 and HER2 was evaluated using immunohistochemistry.
RESULTS: For non-oropharyngeal HNSCC, majority of the cases (66.2%; 102/154) had stage IV disease. EGFR was the most expressed molecular marker (29.4%; 25/85) followed by p53 (24.0%; 29/121), p16 (18.3%; 23/126) and Cyclin-D1 (10.0%; 12/120). HER2 was not expressed in any of the cases. There was a significantly (p = 0.022) higher expression of Cyclin-D1 in tumours of the oral cavity (19.6%; 9/46) than in those of the larynx (4.7%; 2/43) and nose (3.2%; 1/31). Tumours in stages I-III were more frequently positive for p16 (28.6%; 12/42) than tumours in stage IV (13.1%; 11/84).
CONCLUSION: Expression of p53, EGFR, p16 and Cyclin-D1 in non-oropharyngeal HNSCC in Ghana is largely similar to what has been reported in published studies from other countries.

Hélias-Rodzewicz Z, Lourenco N, Bakari M, et al.
CDKN2A Depletion Causes Aneuploidy and Enhances Cell Proliferation in Non-Immortalized Normal Human Cells.
Cancer Invest. 2018; 36(6):338-348 [PubMed] Related Publications
Aneuploidy is a common feature of cancer cells and may contribute to cellular transformation and cancer development. In this study, we found that significant down-regulation of CDKN2A, CHEK2, CDCA8, TP53BP1, and CCNDBP1 led to chromosome imbalances in two diploid non-immortalized human cell lines; however, only CDKN2A inhibition enhanced cell proliferation and additionally up-regulated three cell cycle control genes: CDCA8, AURKA, and CCND. These results confirm that CDKN2A is a tumor suppressor gene driving human cancer development by inducing cell aneuploidy and cell cycle up-regulation.

Cust AE, Mishra K, Berwick M
Melanoma - role of the environment and genetics.
Photochem Photobiol Sci. 2018; 17(12):1853-1860 [PubMed] Related Publications
Melanoma rates have increased in populations that are mainly European. The main etiologic factor is ultraviolet radiation, from the sun as well as artificial tanning devices. Host factors such as skin color, number of nevi, hair and eye color and tanning ability are critical factors in modifying an individual's response to the sun. Genetic factors interact with host factors and environmental factors to increase risk. This review summarizes our current knowledge of environment and genetics on melanoma risk and on gene-environment interaction.

Li J, Li Y, Meng F, et al.
Knockdown of long non-coding RNA linc00511 suppresses proliferation and promotes apoptosis of bladder cancer cells via suppressing Wnt/β-catenin signaling pathway.
Biosci Rep. 2018; 38(4) [PubMed] Free Access to Full Article Related Publications
More and more studies have shown that long non-coding RNAs (lncRNAs) play critical roles in various biological processes of bladder cancer, including proliferation, apoptosis, migration and cell cycle arrest. LncRNA long intergenic noncoding RNA 00511 (linc00511) is one of the lncRNAs highly expressed in bladder cancer tissues and cells. However, little is known about the roles and mechanisms of linc00511 in bladder cancer. Here, we demonstrated that linc00511 was highly expressed in bladder cancer tissues and cells. Linc00511 knockdown could cause the cell proliferation suppression and cell cycle arrest, which were mediated by p18, p21, CDK4, cyclin D1 and phosphorylation Rb. Suppressed linc00511 could induce the apoptosis in T24 and BIU87 cells via activating the caspase pathway. Down-regulation of linc00511 could also suppress the migration and invasion of T24 and BIU87 cells. In addition, we found that the expression of linc00511 was negatively correlated with that of miR-15a-3p in the clinical bladder cancer samples. Further mechanistic studies showed that linc00511 knockdown induced proliferation inhibition, and apoptosis increase might be regulated through suppressing the activities of Wnt/β-catenin signaling pathway. Thus, we revealed that knockdown of linc00511 suppressed the proliferation and promoted apoptosis of bladder cancer cells through suppressing the activities of Wnt/β-catenin signaling pathway. Moreover, we suggested that linc00511 could be a potential therapeutic target and novel biomarker in bladder cancer.

Ma J, Fu Y, Tu YY, et al.
Mutation allele frequency threshold does not affect prognostic analysis using next-generation sequencing in oral squamous cell carcinoma.
BMC Cancer. 2018; 18(1):758 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: With the development of sequencing technologies, there may be some disputes on sequencing analysis. The aim of this study was to investigate different allele frequency thresholds of mutations in targeted genes on prognostic analyses using a panel of cancer associated gene exons (CAGE) in oral squamous cell carcinoma (OSCC).
METHODS: Forty-six patients were included in this study. Twelve genes were sequenced and analyzed using next-generation sequencing from formalin-fixed paraffin-embedded tissues. Allele frequency thresholds of 10, 5, and 3% were used for prognostic analyses.
RESULTS: With a mean sequence depth of 3199-fold, 99% of CAGE were represented by at least 10 reads. Ninety-four non-synonymous (missense [70.2%], nonsense [11.7%], splice site [10.6%], and insertion/deletion [7.5%]) mutations were detected in 40 OSCC patients with an allele frequency threshold of 10%. TP53 (78.3%), NOTCH1 (30.4%), CASP8 (13.0%), CDKN2A (10.9%), and CDH1 (6.5%) were the most frequently mutated genes. Using allele frequency thresholds of 10, 5, and 3%, there were no significant differences in clinical outcomes between patients with non-synonymous mutations and wild type genotypes.
CONCLUSIONS: TP53, NOTCH1, CASP8, CDKN2A, and CDH1 are the most frequently mutated genes in OSCC patients. The allele frequency threshold used in this study does not affect the results of clinical outcome analysis.

Ma HS, Wang EL, Xu WF, et al.
Overexpression of DNA (Cytosine-5)-Methyltransferase 1 (DNMT1) And DNA (Cytosine-5)-Methyltransferase 3A (DNMT3A) Is Associated with Aggressive Behavior and Hypermethylation of Tumor Suppressor Genes in Human Pituitary Adenomas.
Med Sci Monit. 2018; 24:4841-4850 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Alteration of DNA methylation of tumor suppressor genes (TSGs) is one of the most consistent epigenetic changes in human cancers. DNMTs play several important roles in DNA methylation and development of cancers. Regarding DNMTs protein expressions, little is known about the clinical significance and correlation with promoter methylation status of TSGs in human pituitary adenomas. MATERIAL AND METHODS We analyzed the protein expression of 3 DNMTs using immunohistochemistry and assessed DNA hypermethylation of RASSF1A, CDH13, CDH1, and CDKN2A (p16) in 63 pituitary adenomas. We examined associations between DNMTs expression and clinicopathological features or promoter methylation status of TSGs. RESULTS Overexpression of DNMTs was detected in pituitary adenomas. Frequencies of DNMT1 overexpression were significantly higher in macroadenomas, invasive tumors, and grade III and IV tumors. DNMT3A was frequently detected in invasive tumors and grade IV tumors. In addition, DNMT1 and DNMT3A were frequently detected in high-methylation tumors. Furthermore, in multivariate logistic regression, the significant association between DNMT1 or DNMT3A and high-methylation status persisted after adjusting for clinicopathological features. CONCLUSIONS Our findings suggested that tumor overexpression of DNMT1 and DNMT3A is associated with tumor aggressive behavior and high-methylation status in pituitary adenomas. Our data support a possible role of DNMT1 and DNMT3A in TSG promoter methylation leading to pituitary adenoma invasion and suggest that inhibition of DNMTs has the potential to become a new therapeutic approach for invasive pituitary adenoma.

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.

Zięba S, Kowalik A, Zalewski K, et al.
Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets.
Gynecol Oncol. 2018; 150(3):552-561 [PubMed] Related Publications
BACKGROUND: Vulvar squamous cell carcinoma (VSCC) constitutes over 90% of vulvar cancer. Its pathogenesis can follow two different pathways; high risk human papillomavirus (hrHPV)-dependent and HPV-independent. Due to the rarity of VSCC, molecular mechanisms underlying VSCC development remain largely unknown. The study aimed to identify pathogenic mutations implicated in the two pathways of VSCC development.
METHODS: Using next generation sequencing, 81 VSCC tumors, 52 hrHPV(+) and 29 hrHPV(-), were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific).
RESULTS: Mutations of TP53 (46% and 41%, of hrHPV(+) and hrHPV(-) cases respectively) and CDKN2A (p16) (25% and 21%, of hrHPV(+) and hrHPV(-) cases respectively) were the most common genetic alterations identified in VSCC tumors. Further mutations were identified in PIK3CA, FBXW7, HRAS, FGFR3, STK11, AKT1, SMAD4, FLT3, JAK3, GNAQ, and PTEN, albeit at low frequencies. Some of the identified mutations may activate the PI3K/AKT/mTOR pathway. The activation of mTOR was confirmed in the vast majority of VSCC samples by immunohistochemical staining.
CONCLUSIONS: Detecting pathogenic mutations in 13/50 genes examined at comparable frequencies in hrHPV(+) and hrHPV(-) tumors suggest that genetic mechanisms of the two routes of VSCC pathogenesis may be similar, despite being initiated from different premalignant lesions. Importantly, our data provide a rationale for new anti-VSCC therapies targeting the PI3K/AKT/mTOR pathway.

Madhu Krishna B, Chaudhary S, Mishra DR, et al.
Estrogen receptor α dependent regulation of estrogen related receptor β and its role in cell cycle in breast cancer.
BMC Cancer. 2018; 18(1):607 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer (BC) is highly heterogeneous with ~ 60-70% of estrogen receptor positive BC patient's response to anti-hormone therapy. Estrogen receptors (ERs) play an important role in breast cancer progression and treatment. Estrogen related receptors (ERRs) are a group of nuclear receptors which belong to orphan nuclear receptors, which have sequence homology with ERs and share target genes. Here, we investigated the possible role and clinicopathological importance of ERRβ in breast cancer.
METHODS: Estrogen related receptor β (ERRβ) expression was examined using tissue microarray slides (TMA) of Breast Carcinoma patients with adjacent normal by immunohistochemistry and in breast cancer cell lines. In order to investigate whether ERRβ is a direct target of ERα, we investigated the expression of ERRβ in short hairpin ribonucleic acid knockdown of ERα breast cancer cells by western blot, qRT-PCR and RT-PCR. We further confirmed the binding of ERα by electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), Re-ChIP and luciferase assays. Fluorescence-activated cell sorting analysis (FACS) was performed to elucidate the role of ERRβ in cell cycle regulation. A Kaplan-Meier Survival analysis of GEO dataset was performed to correlate the expression of ERRβ with survival in breast cancer patients.
RESULTS: Tissue microarray (TMA) analysis showed that ERRβ is significantly down-regulated in breast carcinoma tissue samples compared to adjacent normal. ER + ve breast tumors and cell lines showed a significant expression of ERRβ compared to ER-ve tumors and cell lines. Estrogen treatment significantly induced the expression of ERRβ and it was ERα dependent. Mechanistic analyses indicate that ERα directly targets ERRβ through estrogen response element and ERRβ also mediates cell cycle regulation through p18, p21
CONCLUSION: Our results indicate that ERRβ is a negative regulator of cell cycle and a possible tumor suppressor in breast cancer. ERRβ could be therapeutic target for the treatment of breast cancer.

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

Karagianni F, Njauw CN, Kypreou KP, et al.
CDKN2A/CDK4 Status in Greek Patients with Familial Melanoma and Association with Clinico-epidemiological Parameters.
Acta Derm Venereol. 2018; 98(9):862-866 [PubMed] Free Access to Full Article Related Publications
Approximately 5-10% of melanoma cases occur in a familial context. CDKN2A/CDK4 were the first high-penetrance melanoma genes identified. The aims of this study were to evaluate CDKN2A/CDK4 variants in Greek familial melanoma patients and to correlate the mutational status with specific clinico-epidemiological characteristics. A cross-sectional study was conducted by genotyping CDKN2A/CDK4 variants and selected MC1R polymorphisms in 52 melanoma-prone families. Descriptive statistics were calculated and comparisons were made using the χ2 test, Fisher's exact test and Student's t-test for statistical analysis, as appropriate. CDKN2A variants were detected in 46.2% of melanoma-prone families, while a CDK4 variant was found in only one family. This study confirmed that, in the Greek population, the age at melanoma diagnosis was lower in patients carrying a variant in CDKN2A compared with wild-type patients. No statistically significant associations were found between CDKN2A mutational status and MC1R polymorphisms.

Ko A, Han SY, Song J
Regulatory Network of ARF in Cancer Development.
Mol Cells. 2018; 41(5):381-389 [PubMed] Free Access to Full Article Related Publications
ARF is a tumor suppressor protein that has a pivotal role in the prevention of cancer development through regulating cell proliferation, senescence, and apoptosis. As a factor that induces senescence, the role of ARF as a tumor suppressor is closely linked to the p53-MDM2 axis, which is a key process that restrains tumor formation. Thus, many cancer cells either lack a functional ARF or p53, which enables them to evade cell oncogenic stress-mediated cycle arrest, senescence, or apoptosis. In particular, the

Cao Z, Wei L, Zhu W, Yao X
Meta-analysis of CDKN2A methylation to find its role in prostate cancer development and progression, and also to find the effect of CDKN2A expression on disease-free survival (PRISMA).
Medicine (Baltimore). 2018; 97(12):e0182 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Reduction of cyclin-dependent kinase inhibitor 2A (CDKN2A) (p16 and p14) expression through DNA methylation has been reported in prostate cancer (PCa). This meta-analysis was conducted to assess the difference of p16 and p14 methylation between PCa and different histological types of nonmalignant controls and the correlation of p16 or p14 methylation with clinicopathological features of PCa.
METHODS: According to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria, articles were searched in PubMed, Embase, EBSCO, Wanfang, and CNKI databases. The strength of correlation was calculated by the pooled odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs). Trial sequential analysis (TSA) was used to estimate the required population information for significant results.
RESULTS: A total of 20 studies published from 1997 to 2017 were identified in this meta-analysis, including 1140 PCa patients and 530 cases without cancer. Only p16 methylation in PCa was significantly higher than in benign prostatic lesions (OR = 4.72, P = .011), but had a similar level in PCa and adjacent tissues or high-grade prostatic intraepithelial neoplasias (HGPIN). TSA revealed that this analysis on p16 methylation is a false positive result in cancer versus benign prostatic lesions (the estimated required information size of 5116 participants). p16 methylation was not correlated with PCa in the urine and blood. Besides, p16 methylation was not linked to clinical stage, prostate-specific antigen (PSA) level, and Gleason score (GS) of patients with PCa. p14 methylation was not correlated with PCa in tissue and urine samples. No correlation was observed between p14 methylation and clinical stage or GS. CDKN2A mutation and copy number alteration were not associated with prognosis of PCa in overall survival and disease-free survival. CDKN2A expression was not correlated with the prognosis of PCa in overall survival (492 cases) (P > .1), while CDKN2A expression was significantly associated with a poor disease-free survival (P < .01).
CONCLUSION: CDKN2A methylation may not be significantly associated with the development, progression of PCa. Although CDKN2A expression had an unfavorable prognosis in disease-free survival. More studies are needed to confirm our results.

Nouhaud FX, Blanchard F, Sesboue R, et al.
Clinical Relevance of Gene Copy Number Variation in Metastatic Clear Cell Renal Cell Carcinoma.
Clin Genitourin Cancer. 2018; 16(4):e795-e805 [PubMed] Related Publications
BACKGROUND: Gene copy number variations (CNVs) have been reported to be frequent in renal cell carcinoma (RCC), with potential prognostic value for some. However, their clinical utility, especially to guide treatment of metastatic disease remains to be established. Our objectives were to assess CNVs on a panel of selected genes and determine their clinical relevance in patients who underwent treatment of metastatic RCC.
PATIENTS AND METHODS: The genetic assessment was performed on frozen tissue samples of clear cell metastatic RCC using quantitative multiplex polymerase chain reaction of short fluorescent fragment method to detect CNVs on a panel of 14 genes of interest. The comparison of the electropherogram obtained from both tumor and normal renal adjacent tissue allowed for CNV identification. The clinical, biologic, and survival characteristics were assessed for their associations with the most frequent CNVs.
RESULTS: Fifty patients with clear cell metastatic RCC were included. The CNV rate was 21.4%. The loss of CDKN2A and PLG was associated with a higher tumor stage (P < .05). The loss of PLG and ALDOB was associated with a higher Fuhrman grade (P < .05). The loss of ALDOB was also associated with a worse Heng prognostic score (95% vs. 66%; P = .029) and lower 24-month survival rate (18% vs. 58%; P = .012). The loss of both ALDOB and PLG was frequent (32%) and was associated with a higher tumor stage and grade (P < .05).
CONCLUSION: As expected, we showed that several CNVs were associated with clinical relevance, especially those located on CDKN2A, PLG, and ALDOB, in a homogeneous cohort of patients with clear cell metastatic RCC.

De Unamuno B, García-Casado Z, Bañuls J, et al.
CDKN2A germline alterations in melanoma patients with personal or familial history of pancreatic cancer.
Melanoma Res. 2018; 28(3):246-249 [PubMed] Related Publications
CDKN2A germline mutations increase the risk of melanoma development and are present in 20 and 10% of familial and multiple melanoma cases, respectively. Pancreatic cancer has been associated with CDKN2A in some populations and, accordingly, its presence in first-degree or second-degree relatives of a melanoma patient is considered as a criterion for genetic testing. In this study, we show that in an area with low melanoma incidence, CDKN2A germline mutations in patients with melanoma and personal or family history of pancreatic cancer are mainly present in the setting of familial or multiple melanoma cases. In addition, a relatively young age (≤52 years) at pancreatic diagnosis is an additional single criterion that might also be considered.

Breyer J, Wirtz RM, Erben P, et al.
High CDKN2A/p16 and Low FGFR3 Expression Predict Progressive Potential of Stage pT1 Urothelial Bladder Carcinoma.
Clin Genitourin Cancer. 2018; 16(4):248-256.e2 [PubMed] Related Publications
BACKGROUND: A recent study on the comprehensive genomic profile of advanced urothelial bladder cancer (UBC) showed cyclin-dependent kinase inhibitor 2A (CDKN2A) and fibroblast growth factor receptor 3 (FGFR3) as the most often clinically relevant genomic alterations. Therefore, the prognostic role of FGFR3 and CDKN2A/p16 for pT1 UBC was studied.
PATIENTS AND METHODS: Clinical data and formalin-fixed paraffin-embedded tissues of pT1 UBC treated with an organ-preserving approach was analyzed retrospectively. Total RNA was isolated using commercial RNA extraction kits and mRNA expression of CDKN2A/p16 and FGFR3 was measured using single step reverse transcription quantitative real time polymerase chain reaction using RNA-specific TaqMan assays.
RESULTS: Data from 296 patients (79.4% male; median age: 72 years) could be used for the final evaluation. Spearman correlation revealed a statistically significant negative correlation between mRNA expression of CDKN2A/p16 and FGFR3. There was a positive correlation between CDKN2A/p16 and G3 tumors (ρ = 0.1875; P = .0012) and associated carcinoma in situ (ρ = 0.1703, P = .0033) and a negative correlation between FGFR3 and these factors (ρ = -0.2791, P < .0001 and ρ = -0.2182, P = .0002). High CDKN2A/p16 expression (≥38.04) and low FGFR3 expression (<39.14) were statistically significantly associated with worse progression-free survival (PFS; P = .0194 and P = .0089). Multivariate Cox regression analysis could identify patients with low FGFR3 and high CDKN2A/p16 expression (log rank (LR) χ
CONCLUSION: High expression of CDKN2A/p16 and low expression of FGFR3 show a correlation with established prognostic features for non-muscle-invasive bladder cancer and can predict progression of stage pT1 UBC.

Müller C, Krunic M, Wendt J, et al.
Germline Variants in the POT1-Gene in High-Risk Melanoma Patients in Austria.
G3 (Bethesda). 2018; 8(5):1475-1480 [PubMed] Free Access to Full Article Related Publications
Risk of melanoma is in part determined by genetic factors. Currently the only established high penetrance familial melanoma genes are CDKN2A and CDK4. Recent studies reported germline variants in POT1 in melanoma families. In the present study, we sequenced the entire POT1 gene in 694 patients from the M3-study. Patients with multiple primary melanomas (n = 163) or with a positive family history (n = 133) were classified as high-risk melanoma patients. Additionally, 200 single primary melanoma patients and 198 non-melanoma controls were sequenced. For prediction analysis 10 different tools were used.In total 53 different variants were found, of which 8 were detected in high-risk melanoma patients, only. Two out of these 8 variants were located in exons and were non-synonymous: g.124510982 G>A (p.R80C) and g.124491977 T>G (p.N300H). While g.124491977 T>G was predicted to be neutral, 80% of the prediction tools classified g.124510982 G>A as deleterious. The variant, g.124467236 T>C, which possibly causes a change in the splice site was identified in a case with a positive family history in the present study. Another variant in the 5-UTR, g.124537261 A>G, was found in 2 high-risk patients. So, in conclusion, melanoma associated POT1 germline variants seem to be rare. Further studies are required to evaluate the role of POT1 for genetic counseling.

Roy S, LaFramboise WA, Liu TC, et al.
Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times.
Gastroenterology. 2018; 154(8):2060-2063.e8 [PubMed] Free Access to Full Article Related Publications
Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease-free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease-free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs.

Wang Y, Tian Y, Lin J, et al.
Assessment of p16 expression and HPV infection in adenoid cystic carcinoma of the lacrimal gland.
Mol Vis. 2018; 24:143-152 [PubMed] Free Access to Full Article Related Publications
Purpose: Adenoid cystic carcinoma (ACC) in the lacrimal gland is a rare malignancy. P16 is encoded by the
Methods: Twenty-one ACCs in the lacrimal gland and ten matched healthy lacrimal glands were studied. P16 was detected with immunohistochemistry (IHC), and HPV was detected with in situ hybridization (ISH) and PCR in all cases. Other cell cycle proteins were also detected with IHC, including cyclin D1 and Ki67. The methylation status of the p16 promoter was detected with methylation-specific PCR (MSP) to further investigate the regulation of p16 expression.
Results: The expression rates of p16 (47.6%, 10/21), cyclin D1 (100%, 21/21), and Ki67 (52.4%, 11/21) were increased in ACCs compared to healthy lacrimal glands (negative). The results showed p16 expression was limited to the inner ductal epithelial cells in the majority of the tubular and cribriform patterns. In solid ACCs, p16 was uniformly positive. HPV was negative in all 21 cases with ISH and PCR. P16 overexpression was associated with cyclin D1 overexpression (p=0.013). Only 13 cases were tested successfully with MSP. The expression rate of p16 methylation was 23.1% (3/13) of the ACCs. Compared with primary ACCs, recurrent ACCs showed higher p16, cyclin D1, and Ki67 expression (p=0.011, p=0.026, p=0.049, respectively).
Conclusions: In summary, p16 overexpression was cell-type dependent in ACCs in the lacrimal gland, while HPV infection was negative. P16 overexpression was unrelated to HPV infection. The mechanism of p16 overexpression needs to be further investigated in ACCs in the lacrimal gland.

Huerta C, Garcia-Casado Z, Bañuls J, et al.
Characteristics of Familial Melanoma in Valencia, Spain, Based on the Presence of CDKN2A Mutations and MC1R Variants.
Acta Derm Venereol. 2018; 98(5):512-516 [PubMed] Related Publications
Melanoma results from a complex interplay between environmental factors and individual genetic susceptibility. Familial melanoma is attributable to predisposition genes with variable penetrance. The aim of this study was to identify differences between familial melanoma and sporadic cases in our population, based on the presence of CDKN2A mutations and MC1R variants. Comparing 107 patients with familial melanoma from 87 families (17% CDKN2A mutated) with 1,390 cases of sporadic melanomas, the former were younger and exhibited an increased prevalence of atypical naevi and squamous cell carcinoma (SCC). CDKN2A mutation carriers presented more atypical naevi, multiple melanomas, and basal cell carcinoma, while non-carriers were more likely to have light-coloured hair, atypical naevi, and SCC. MC1R variants decreased the age at diagnosis in all groups and were associated with an increased prevalence of SCC, especially in patients with familial melanoma without CDKN2A mutations. These characteristics may help to establish prevention measures targeting patients with familial melanoma in the Mediterranean area.

Dubot C, Bernard V, Sablin MP, et al.
Comprehensive genomic profiling of head and neck squamous cell carcinoma reveals FGFR1 amplifications and tumour genomic alterations burden as prognostic biomarkers of survival.
Eur J Cancer. 2018; 91:47-55 [PubMed] Related Publications
BACKGROUND: We aimed at identifying deleterious genomic alterations from untreated head and neck squamous cell carcinoma (HNSCC) patients, and assessing their prognostic value.
PATIENTS AND METHODS: We retrieved 122 HNSCC patients who underwent primary surgery. Targeted NGS was used to analyse a panel of 100 genes selected among the most frequently altered genes in HNSCC and potential therapeutic targets. We selected only deleterious (activating or inactivating) single nucleotide variations, and copy number variations for analysis. Univariate and multivariate analyses were performed to assess the prognostic value of altered genes.
RESULTS: A median of 2 (range: 0-10) genomic alterations per sample was observed. Most frequently altered genes involved the cell cycle pathway (TP53 [60%], CCND1 [30%], CDKN2A [25%]), the PI3K/AKT/MTOR pathway (PIK3CA [12%]), tyrosine kinase receptors (EGFR [9%], FGFR1 [5%]) and cell differentiation (FAT1 [7%], NOTCH1 [4%]). TP53 mutations (p = 0.003), CCND1 amplifications (p = 0.04), CDKN2A alterations (p = 0.02) and FGFR1 amplifications (p = 0.003), correlated with shorter overall survival (OS). The number of genomic alterations was significantly higher in the HPV-negative population (p = 0.029) and correlated with a shorter OS (p < 0.0001). Only TP53 mutation and FGFR1 amplification status remained statistically significant in the multivariate analysis.
CONCLUSION: These results suggest that genomic alterations involving the cell cycle (TP53, CCND1, CDKN2A), as well as FGFR1 amplifications and tumour genomic alterations burden are prognostic biomarkers and might be therapeutic targets for patients with HNSCC.

Shah K, Patel S, Mirza S, Rawal RM
Unravelling the link between embryogenesis and cancer metastasis.
Gene. 2018; 642:447-452 [PubMed] Related Publications
PURPOSE: Cancer as opposed to embryonic development is characterized by dysregulated, uncontrolled and clonal growth of cells. Inspite of that they share certain commonality in gene expression patterns and a number of cellular & molecular features. Consequently, in the present study we aimed to evaluate the role of a definite set of genes in fetal liver, primary liver cancers and metastatic liver tissue.
METHODS: The relative expression of fourteen candidate genes obtained by data mining and manual curation of published data (CXCL12, CXCR4, CK7, CDH1, CTNNB1, CLDN4, VEGFA, HIF1A, MMP9, p53, OPN, CDKN2A, TGFBR2, MUC16, β-actin) were performed on 62 tissues (32 liver metastasis tissues and 30 primary Liver cancer tissues), Fetal liver tissues (below and above 20weeks of gestation) and 2 sets of control samples by real-time quantitative reverse transcription PCR (qRT-PCR).
RESULTS: Results showed significant down-regulation of MMP9 and TP53 in Fetal liver above 20weeks of gestation whereas it was up-regulated in fetal liver below 20weeks of gestation, primary liver cancers and liver metastasis. Contradictory to that OPN and CDKN2A were significantly up-regulated in primary liver cancer, liver metastasis; down-regulated in fetal liver above 20weeks of gestation but were not expressed during early embryo development (below 20weeks of gestation). Moreover, MMP9 and TP53 demonstrated a strong correlation with MUC16 whereas CDKN2A and OPN showed correlation with CXCL12/CXCR4 signifying that MUC16, CXCL12/CXCR4 might be involved in the complex process of cancer metastasis.
CONCLUSION: MMP9, OPN, TP53 and CDKN2A were the identified markers that were expressed in a similar pattern in early embryonic development and cancer development & invasion suggesting that these genes are activated during embryogenesis and might be re-expressed in cancer metastasis. Moreover, these genes govern a pathway that might be activated during cancer metastasis. Thus, targeting these molecules may provide better treatment for metastatic liver cancers.

Saunderson EA, Stepper P, Gomm JJ, et al.
Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors.
Nat Commun. 2017; 8(1):1450 [PubMed] Free Access to Full Article Related Publications
Aberrant promoter DNA hypermethylation is a hallmark of cancer; however, whether this is sufficient to drive cellular transformation is not clear. To investigate this question, we use a CRISPR-dCas9 epigenetic editing tool, where an inactive form of Cas9 is fused to DNA methyltransferase effectors. Using this system, here we show simultaneous de novo DNA methylation of genes commonly methylated in cancer, CDKN2A, RASSF1, HIC1 and PTEN in primary breast cells isolated from healthy human breast tissue. We find that promoter methylation is maintained in this system, even in the absence of the fusion construct, and this prevents cells from engaging senescence arrest. Our data show that the key driver of this phenotype is repression of CDKN2A transcript p16 where myoepithelial cells harbour cancer-like gene expression but do not exhibit anchorage-independent growth. This work demonstrates that hit-and-run epigenetic events can prevent senescence entry, which may facilitate tumour initiation.

de Sousa SF, Diniz MG, França JA, et al.
Cancer genes mutation profiling in calcifying epithelial odontogenic tumour.
J Clin Pathol. 2018; 71(3):279-283 [PubMed] Related Publications
AIMS: To identify calcifying epithelial odontogenic tumour (CEOT) mutations in oncogenes and tumour suppressor genes.
METHODS: A panel of 50 genes commonly mutated in cancer was sequenced in CEOT by next-generation sequencing. Sanger sequencing was used to cover the region of the frameshift deletion identified in one sample.
RESULTS: Missense single nucleotide variants (SNVs) with minor allele frequency (MAF) <1% were detected in
CONCLUSION: CEOT harbours mutations in the tumour suppressor

Shah V, Boyd KD, Houlston RS, Kaiser MF
Constitutional mutation in CDKN2A is associated with long term survivorship in multiple myeloma: a case report.
BMC Cancer. 2017; 17(1):718 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple Myeloma is a cancer of plasma cells associated with significantly reduced survival. Long term survivorship from myeloma is very rare and despite advances in its treatment the disease is generally considered incurable. We report a patient diagnosed with myeloma carrying a germline mutation of a tumour suppressor gene who has effectively been cured.
CASE PRESENTATION: A 36-year-old woman was diagnosed with IgG lambda myeloma in 1985. She was treated with melphalan chemotherapy followed by high-dose melphalan and autologous stem cell rescue and since remained in complete remission despite not having received any additional therapy. After eliciting a prior history of multiple primary melanomas and breast cancer, she was tested for and shown to be a carrier for a germline mutation in CDKN2A.
CONCLUSIONS: This is the second case report of germline mutation of CDKN2A being associated with myeloma. CDKN2A is a stabiliser of p53. Long term survivorship after high dose DNA damaging chemotherapy with melphalan in this patient is compatible with an increased chemo-sensitivity due to impairment of the DNA repair pathway.

El Naofal M, Kim A, Yon HY, et al.
Role of CDKN2C Fluorescence In Situ Hybridization in the Management of Medullary Thyroid Carcinoma.
Ann Clin Lab Sci. 2017; 47(5):523-528 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC), an aggressive form of thyroid cancer, occurs sporadically in approximately 75% of MTCs.

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