Gene Summary

Gene:PLCE1; phospholipase C, epsilon 1
Aliases: PLCE, PPLC, NPHS3
Summary:This gene encodes a phospholipase enzyme that catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to generate two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). These second messengers subsequently regulate various processes affecting cell growth, differentiation, and gene expression. This enzyme is regulated by small monomeric GTPases of the Ras and Rho families and by heterotrimeric G proteins. In addition to its phospholipase C catalytic activity, this enzyme has an N-terminal domain with guanine nucleotide exchange (GEF) activity. Mutations in this gene cause early-onset nephrotic syndrome; characterized by proteinuria, edema, and diffuse mesangial sclerosis or focal and segmental glomerulosclerosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Sep 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1
Source:NCBIAccessed: 06 August, 2015


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 (1990-2015)
Graph generated 06 August 2015 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.

  • MUC1
  • Basic-Leucine Zipper Transcription Factors
  • Lymphatic Metastasis
  • Linkage Disequilibrium
  • Case-Control Studies
  • Esophageal Cancer
  • Kazakhstan
  • European Continental Ancestry Group
  • Immunoenzyme Techniques
  • Staging
  • Transcription Factors
  • Alleles
  • Polymerase Chain Reaction
  • Neoplasm Proteins
  • Genetic Loci
  • Ubiquitin-Protein Ligases
  • Colorectal Cancer
  • Haplotypes
  • Apoptosis
  • Squamous Cell Carcinoma
  • Smoking
  • Messenger RNA
  • Asian Continental Ancestry Group
  • Polymorphism
  • Follow-Up Studies
  • China
  • RT-PCR
  • Genotype
  • Genetic Predisposition
  • Genome-Wide Association Study
  • Adenocarcinoma
  • Chromosome 10
  • Odds Ratio
  • Risk Factors
  • Tumor Antigens
  • Restriction Fragment Length Polymorphism
  • Phosphoinositide Phospholipase C
  • Membrane Transport Proteins
Tag cloud generated 06 August, 2015 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: PLCE1 (cancer-related)

Kupcinskas J, Wex T, Link A, et al.
PSCA and MUC1 gene polymorphisms are associated with gastric cancer and pre-malignant gastric conditions [corrected].
Anticancer Res. 2014; 34(12):7167-75 [PubMed] Related Publications
BACKGROUND/AIM: Genome-wide association studies revealed a link between gastric cancer (GC) and single nucleotide polymorphisms (SNPs) of prostate stem cell antigen (PSCA), phospholipase C epsilon-1 (PLCE1) and mucin-1 (MUC1) genes. Herein, we aimed to evaluate associations between PSCA (C>T, rs2294008; G>A, rs2976392), MUC1 (C>T, rs4072037) and PLCE1 (A>G, rs2274223) SNPs and GC or high-risk gastritis (HRAG).
MATERIALS AND METHODS: Using TaqMan system, SNPs were genotyped in 252 patients with GC, 136 patients with HRAG and 246 controls.
RESULTS: PSCA rs2294008 allele T was associated with risk of GC (odds ratio (OR)=1.88, p<0.001) and HRAG (OR=1.49, p=0.009). Allele A of PSCA rs2976392 was associated with development of GC (OR=1.88, p<0.001) and HRAG (OR=1.56, p<0.01). MUC1 rs4072037 allele G was protective against development of GC (OR=0.64, p=0.0005), while no differences were found for PLCE1 rs2274223.
CONCLUSION: Polymorphisms of PSCA (rs2976392, rs2294008) and MUC1 (rs4072037) genes are associated with GC and HRAG.

Guo LY, Yang N, Hu D, et al.
PLCE1 rs2274223 polymorphism and susceptibility to esophageal cancer: a meta-analysis.
Asian Pac J Cancer Prev. 2014; 15(21):9107-12 [PubMed] Related Publications
PURPOSE: To investigate and study the relationship between the PLCE1 rs2274223 gene polymorphism and susceptibility to esophageal cancer by meta-analysis.
MATERIALS AND METHODS: The literature was searched in Wanfang, CNKI, PubMed, CBM, Web of Science, MEDLINE, EMBASE, Springer, Elsevier and Cochrane databases from the date of January 1st 2004 to April 1st 2014 to collect case-control studies on the PLCE1 polymorphism and susceptibility to esophageal cancer. For the population genotype distributions of both esophagus cancer and control groups, their odds ratios (ORs) and 95% confidence intervals (CIs) were taken as effect indexes. Disqualified studies were excluded. Odds ratios of PLCE1 rs2274223 genotype distributions in the group of patients with esophageal cancer and the group of healthy control were calculated. The meta- analysis software, RevMan5.0, was applied for heterogeneity test, pooled OR and 95% confidence intervals. Sensitivity analysis and publication bias were also explored.
RESULTS: A total of twelve case-control studies were included, covering a total of 9, 912 esophageal cancer cases and 13, 023 controls were included. The pooled odds ratio of PLCE1 rs2274223 genotype GA vs AA was 1.29 (95%CI=1.17~1.43), p<0.01, GG vs AA was 1.65 (95%CI=1.32~2.05), p<0.01, GG/GA vs AA was 1.30 (95%CI=1.16~1.46), p<0.01 and GG vs GA/AA was 1.48 (95%CI=1.22~1.80), p<0.01. The PLCE1 rs2274223 polymorphism was thus associated with risk of esophageal cancer in all genetic models. In the stratified analysis by ethnicity, and source of controls, no significantly increased risk was observed for white persons. There was no obvious publication bias detected.
CONCLUSIONS: This meta-analysis showed there was a significantly association between PLCE1 rs2274223 polymorphism and esophageal cancer in yellow race populations. Due to some minor limitations, our findings should be confirmed in further studies.

Lo Vasco VR, Leopizzi M, Stoppoloni D, Della Rocca C
Silencing of phosphoinositide-specific phospholipase C ε remodulates the expression of the phosphoinositide signal transduction pathway in human osteosarcoma cell lines.
Anticancer Res. 2014; 34(8):4069-75 [PubMed] Related Publications
BACKGROUND: Ezrin, a member of the ezrin-radixin-moesin family, is involved in the metastatic spread of osteosarcoma. Ezrin binds phosphatydil inositol-4,5-bisphosphate (PIP2), a crucial molecule of the phosphoinositide signal transduction pathway. PIP2 levels are regulated by phosphoinositide-specific phospholipase C (PI-PLC) enzymes. PI-PLCε isoform, a well-characterized direct effector of rat sarcoma (RAS), is at a unique convergence point for the broad range of signaling pathways that promote RAS GTPase-mediated signalling.
MATERIALS AND METHODS: By using molecular biology methods and microscopic analyses, we analyzed the expression of ezrin and PLC genes after silencing of PLCE (OMIM *608414) in 143B and Hs888 cell lines.
RESULTS: The growth rate of the cells was slowed, and the expression of ezrin, PLCB1, PLCG2 and PLCD4 was significantly modified. Ezrin displacement from the plasma membrane was observed.
CONCLUSION: The present results corroborate the hypothesis that ezrin and the PI signal transduction system are involved in a common network.

Zhao L, Wei ZB, Yang CQ, et al.
Effects of PLCE1 gene silencing by RNA interference on cell cycling and apoptosis in esophageal carcinoma cells.
Asian Pac J Cancer Prev. 2014; 15(13):5437-42 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the most malignancies with a poor prognosis. The phospholipase C? gene (PLCE1) encodes a novel ras-related protein effector mediating the effects of R-Ras on the actin cytoskeleton and membrane protrusion. However, molecular mechanisms pertinent to ESCC are unclear. We therefore designed PLCE1-special small interfering RNA and transfected to esophageal squamous cell (EC) 9706 cells to investigate the effects of PLCE1 gene silencing on the cell cycle and apoptosis of ESCC and indicate its important role in the development of ESCC. Esophageal cancer tissue specimens and normal esophageal mucosa were obtained and assayed by immunohistochemical staining to confirm overexpression of PLCE1 in neoplasias. Fluorescence microscopy was used to examine transfection efficiency, while the result of PLCE1 silencing was examined by reverse transcription (RT-PCR). Flow cytometry and annexin V apoptosis assays were used to assess the cell cycle and apoptosis, respectively. Expression of cyclin D1 and caspase-3 was detected by Western-blotting. The level of PLCE1 protein in esophageal cancer tissue was significantly higher than that in normal tissue. After transfection, the expression of PLCE1 mRNA in EC 9706 was significantly reduced, compared with the control group. Furthermore, flow cytometry results suggested that the PLCE1 gene silencing arrested the cell cycle in the G0/G1 phase; apoptosis was significantly higher than in the negative control group and mock group. PLCE1 gene silencing by RNAi resulted in decreased expression of cyclin D1 and increased expression of caspase-3. Our study suggests that PLCE1 may be an oncogene and play an important role in esophageal carcinogenesis through regulating proteins which control cell cycling and apoptosis.

Yang J, Wu H, Wei S, et al.
HPV seropositivity joints with susceptibility loci identified in GWASs at apoptosis associated genes to increase the risk of Esophageal Squamous Cell Carcinoma (ESCC).
BMC Cancer. 2014; 14:501 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We previously showed that human papillomavirus (HPV) serostatus was not an independent risk factor for esophageal squamous cell carcinoma(ESCC) in nonsmokers and nondrinkers; however, HPV increased the risk in smokers.
METHODS: Here we investigated possible interactions between HPV16 serostatus and three susceptibility loci identified in GWASs at apoptosis associated genes with regard to risk of ESCC in a case-control study of 313 patients with ESCC and 314 healthy controls. The loci (CHK2 rs738722, C12orf51 rs2074356, and PLCE1 rs2274223) were genotyped, and the presence or absence of HPV16 in serum was measured by ELISA. Multivariable logistic regression was used to evaluate possible interactions of HPV16 serostatus and the three loci on the risk of ESCC.
RESULTS: A significant interaction was found between HPV16 serology and rs2074356 (P = 0.005, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.11-1.77) or rs2274223 (P < 0.001, OR 1.53, 95% CI 1.23-1.91), but not for rs738722. For rs2074356, risk of ESCC was increased substantially in smokers (P < 0.001, OR 8.25, 95% CI 3.84-17.71) and drinkers (OR4.04, P = 0.001, 95% CI 1.79-9.10) who carried risk alleles (TT or TC genotype) and were HPV16-seropositive. Similar results were observed for rs2274223 in smokers (P < 0.001, OR6.06, 95% CI 2.85-12.88) and drinkers (P < 0.001, OR 5.43, 95% CI 2.51-11.76), but not for rs738722.
CONCLUSION: Consistent with the previous study, loci at rs2074356 and rs2274223 could increase the risk of ESCC, furthermore, there were significant interactions between HPV sero-status and the susceptibility loci on the risk of ESCC. This effect could be modified obviously by smoking and drinking.

Liu X, Zhang X, Wang Z, et al.
Genetic polymorphism of the phospholipase C epsilon 1 gene and risk of gastric cancer.
Chin Med J (Engl). 2014; 127(13):2511-7 [PubMed] Related Publications
BACKGROUND: The pathogenesis of gastric cancer (GC) involves environmental and genetic factors. Recently, two genome-wide association studies found that phospholipase C epsilon 1 (PLCE1) polymorphisms might be related to GC risk, and several studies further validated this finding. However, these studies yielded inconsistent results.
METHODS: A comprehensive database search was performed to identify eligible studies. Odds ratios with 95% confidence intervals were calculated to assess the strength of the association between PLCE1 rs2274223, rs753724, and rs11187842 and risk of GC. Subgroup analyses, publication bias, and sensitivity analyses were also conducted.
RESULTS: Eleven studies (12 cohorts) were included in the meta-analysis. Based on 13 676 cases and 23 569 controls, a significant association between PLCE1 rs2274223 and GC risk was detected under various genotypic models. In the subgroup analyses, the association was significant for cardia GC, but weak for non-cardia GC. The association under the heterozygote model was detected for PLCE1 rs753724 and rs11187842 based on three studies involving 2768 cases and 3890 controls.
CONCLUSIONS: Our findings demonstrate that the presence of the G allele at rs2274223 of the PLCE1 gene may contribute to susceptibility to GC, especially cardia GC. PLCE1 rs753724 and rs11187842 are associated with GC risk under the heterozygote model. Further well-designed large studies are warranted to validate these findings.

Ko JM, Zhang P, Law S, et al.
Identity-by-descent approaches identify regions of importance for genetic susceptibility to hereditary esophageal squamous cell carcinoma.
Oncol Rep. 2014; 32(2):860-70 [PubMed] Related Publications
Worldwide, the highest prevalence of esophageal cancer (EC) occurs in Northern China. High-density SNP arrays allow identification of identity-by-descent (IBD) segments in genomic DNAs representative of shared common ancestral regions. We utilized IBD approaches to map susceptibility loci associated with low-penetrance SNPs in high-risk Henan hereditary esophageal squamous cell carcinoma (ESCC) patients. Affymetrix GeneChip Human mapping SNP array IBD analysis was performed in 32 Henan family history-positive (FH+) ESCC patients, 18 Henan healthy unrelated individuals, and 45 Chinese individuals from a CHB HapMap dataset using PLink (scoring IBD segments individually) and Beagle (scoring of shared IBD segments among case/case vs. control/control pairs) software. Both analyses identified longer IBD segment lengths associated with FH+ ESCC compared to controls. However, there was no strong evidence for a genetic founder effect. Pairing IBD analysis with BEAGLE identified 8 critical IBD segments residing at 2q32.1-q32.2, 3p22.3-p22.2, 4q21.1-q21.21, 7p22.2, 8q23.2-q23.3, 10q23.33-q24.1, 14q24.3 and 16q11.2-q12.1, which were more significantly shared among case/case compared to control/control. The shared IBD segments in FH+ ESCC samples with no overlap with control/CHB Hapmap may encompass potential cancer susceptibility loci. Selected targeted genes, PLCE1, GPT2, SIAH1 and CYP2C-18, residing within the IBD segments at 10q23.33-q24.1 and 16q11.2-q12.1, had statistically significant differential expression in primary ESCC tissues and are likely involved in ESCC carcinogenesis. The importance of these IBD segments to the etiology and development of ESCC in high-risk areas requires further study with expanded sample sizes. This is the first report employing the pairing IBD approach for elucidation of the genetic basis of hereditary ESCC in Henan by applying high throughput SNP array analysis.

Sharma KL, Rai R, Srivastava A, et al.
A multigenic approach to evaluate genetic variants of PLCE1, LXRs, MMPs, TIMP, and CYP genes in gallbladder cancer predisposition.
Tumour Biol. 2014; 35(9):8597-606 [PubMed] Related Publications
Gallbladder cancer (GBC) is a violent neoplasm associated with late diagnosis, unsatisfactory treatment, and poor prognosis. The disease shows complex interplay between multiple genetic variants. We analyzed 15 polymorphisms in nine genes involved in various pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were matrix metalloproteinases (MMP-2, MMP-7, and MMP-9), tissue inhibitor of metalloproteinases (TIMP-2), cytochrome P450 (CYP)1A1, CYP1B1, phospholipase C epsilon 1 (PLCE1), liver X receptor (LXR)-alpha, and LXR-beta. Genotypes were determined by PCR-RFLP and TaqMan probes. Statistical analysis was done by SPSS version 16. Multilocus analysis was performed by Classification and Regression Tree (CART) analysis and multifactor dimensionality reduction (MDR) to gene-gene interactions in modifying GBC risk. In silico analysis was done using various bioinformatics tools (F-SNP, FAST-SNP). Single locus analysis showed association of MMP-2 (-735 C > T, -1306 C > T), MMP-7 - 181 A > G, MMP-9 (P574R, R668Q), TIMP-2 - 418 G > C, CYP1A1-MspI, CYP1A1-Ile462Val, PLCE1 (rs2274223 A > G, rs7922612 T > C) and LXR-beta T > C (rs3546355 G > A, rs2695121 T > C) polymorphisms with GBC risk (p < 0.05) whereas CYP1B1 and LXR-α variants were not associated with GBC risk. Multidimensional reduction analysis revealed LXR-β (rs3546355 G > A, rs2695121 T > C), MMP-2 (-1306 C > T), MMP-9 (R668Q), and PLCE1 rs2274223 A > G to be key players in GBC causation (p < 0.001, CVC = 7/10). The results were further supported by independent CART analysis (p < 0.001). In silico analysis of associated variants suggested change in splicing or transcriptional regulation. Interactome and STRING analysis showed network of associated genes. The study found PLCE1 and LXR-β network interactions as important contributory factors for genetic predisposition in gallbladder cancer.

Li Y, An J, Huang S, et al.
PLCE1 suppresses p53 expression in esophageal cancer cells.
Cancer Invest. 2014; 32(6):236-40 [PubMed] Related Publications
The apoptotic mechanism dysfunction plays a critical role in cancer cell growth and escaping from cancer therapies; the underlying mechanisms are to be further elucidated. This study aims to investigate the role of phospholipase C epsilon 1 (PLCE1) in modulating the apoptosis mechanism in esophageal cancer (Eca) cells. The results showed that Eca cell lines, OE33 and CP-C cells expressed high levels of PLCE1. Knockdown of PLCE1 markedly increased 9.26 folds of the expression of p53 and 13.8 folds of the frequency of apoptotic CP-C cells via modulating the p53 promoter methylation.

Martins M, McCarthy A, Baxendale R, et al.
Tumor suppressor role of phospholipase C epsilon in Ras-triggered cancers.
Proc Natl Acad Sci U S A. 2014; 111(11):4239-44 [PubMed] Free Access to Full Article Related Publications
Phospholipase Cε (PLCε) has been characterized as a direct effector of Ras in vitro and in cellular systems; however, the role of PLCε in tumorigenesis and its link to Ras in this context remain unclear. To assess the role of PLCε in Ras-driven cancers, we generated two new mouse strains: one carrying a targeted deletion of Plce (Plce(-/-)) and the other carrying mutant alleles of Plce unable to bind to Ras (Plce(RAm/RAm)). The Plce(-/-) and, to a lesser degree, Plce(RAm/RAm) transgenic mice exhibited increased susceptibility to tumor formation in the two-stage skin carcinogenesis protocol, revealing a tumor suppressor function for this PLC. This result also suggests that in this context Ras binding in part regulates functions of PLCε. Although significant differences were not seen in the LSL-Kras(G12D) nonsmall cell lung carcinoma model, down-regulation of PLCε was found in animal tumors and in cellular systems following expression of the oncogenic Ras. An inhibitory impact of PLCε on cell growth requires intact lipase activity and is likely mediated by protein kinase C enzymes. Further cellular studies suggest involvement of histone deacetylase in the mechanism of PLCε down-regulation. Taken together, our results show a previously unidentified tumor suppressor role for this PLC in animal models and, together with observations of marked down-regulation in colorectal, lung, and skin tumors, suggest its use as a biological marker in cancer.

Shuman Moss LA, Jensen-Taubman S, Rubinstein D, et al.
Dietary intake of a plant phospholipid/lipid conjugate reduces lung cancer growth and tumor angiogenesis.
Carcinogenesis. 2014; 35(7):1556-63 [PubMed] Free Access to Full Article Related Publications
It is well recognized that early detection and cancer prevention are significant armaments in the 'war against cancer'. Changes in lifestyle and diet have significant impact on the global incidence of cancer. For over 30 years, many investigators have studied the concept of chemoprevention. More recently, with the demonstration that antiangiogenic activity reduces tumor growth, the concept of angioprevention has emerged as a novel strategy in the deterrence of cancer development (carcinogenesis). In this study, we utilized a fast growing, highly aggressive murine Lewis lung cancer model to examine the in vivo antitumor effects of a novel, dietary supplement, known as plant phospholipid/lipid conjugate (pPLC). Our goal was to determine if pPLC possessed direct antitumor activity with relatively little toxicity that could be developed as a chemoprevention therapy. We used pPLC directly in this in vivo model due to the lack of aqueous solubility of this novel formulation, which precludes in vitro experimentation. pPLC contains known antioxidants, ferulic acid and lipoic acid, as well as soy sterols, formulated in a unique aqueous-insoluble matrix. The pPLC dietary supplement was shown to suppress in vivo growth of this tumor model by 30%. We also demonstrated a significant decrease in tumor angiogenesis accompanied by increased apoptosis and present preliminary evidence of enhanced expression of the hypoxia-related genes pentraxin-3 and metallothionein-3, by 24.9-fold and 10.9-fold, respectively, compared with vehicle control. These findings lead us to propose using this plant phosolipid/lipid conjugate as a dietary supplement that may be useful in cancer prevention.

Wang Q, Chen P, Chen D, et al.
Association between phospholipase C epsilon gene (PLCE1) polymorphism and colorectal cancer risk in a Chinese population.
J Int Med Res. 2014; 42(2):270-81 [PubMed] Related Publications
OBJECTIVE: To investigate the association between a single nucleotide polymorphism rs2274223 (adenine [A] to guanine [G]) in the phospholipase C epsilon 1 (PLCE1) gene and susceptibility to colorectal cancer (CRC).
METHODS: The PLCE1 rs2274223 polymorphism was genotyped in patients with CRC and age- and sex-matched cancer-free control subjects from a Chinese population in a case-control study. PLCE1 mRNA levels in pair-matched tumour and adjacent noncancerous tissue were evaluated by real-time quantitative reverse transcription-polymerase chain reaction.
RESULTS: A total of 417 patients with CRC and 416 control subjects were enrolled in the study. The AG and GG genotypes of PLCE1 rs2274223 were associated with a significantly increased risk of CRC (for AG + GG versus AA: adjusted odds ratio 1.52, 95% confidence interval 1.15, 2.00). PLCE1 mRNA levels were significantly lower in tumours than in adjacent noncancerous tissue. Lower levels of PLCE1 mRNA were observed in both AG and GG genotype carriers compared with the AA genotype carriers.
CONCLUSIONS: These results indicate that the PLCE1 rs2274223 A > G change might reduce gene expression and that the variant G genotype might contribute to the increased risk of CRC.

Cui XB, Pang XL, Li S, et al.
Elevated expression patterns and tight correlation of the PLCE1 and NF-κB signaling in Kazakh patients with esophageal carcinoma.
Med Oncol. 2014; 31(1):791 [PubMed] Related Publications
This study investigated the expression of the phospholipase C epsilon 1 (PLCE1) and nuclear factor-kappaB (NF-κB)-related proteins in Kazakh patients with esophageal squamous cell carcinoma (ESCC). Tissue microarrays of 90 ethnic Kazakh patients with ESCC and exhibiting clinical characteristics were analyzed for protein expression of PLCE1, IKKβ, IKBα, p50, and p65 by immunohistochemistry. Correlations between histoscores of PLCE1 and NF-κB-related proteins were determined using Spearman's rank correlation tests. Expression of PLCE1 and NF-κB-related proteins significantly increased in tumor tissues compared with normal esophageal tissues (P = 9.48 × 10(-7), 1.24 × 10(-5), 0.004, 0.003, and 2.83 × 10(-5), respectively). Upregulation of PLCE1 was significantly correlated with advanced tumor-node-metastasis stages (P = 0.018) and lymph node metastasis (P = 0.003). Overexpression of IKKβ and IKBα was associated with ESCC stages I/II (P = 3.36 × 10(-4) and 0.022, respectively). Increased expression of p50 was significantly higher in patients with lymph node metastasis than without lymph node metastasis (P = 0.048). Elevated expression of p65 protein was significantly correlated with poor and moderately differentiated ESCC and depth of tumor invasion (P = 0.026 and 0.010, respectively). Significant positive correlations were observed between the expression of PLCE1 and NF-κB-related proteins, especially IKKβ (r = 0.246 and P = 0.025) and p50 (r = 0.244 and P = 0.024). These results suggest, for the first time, that upregulation of PLCE1 is correlated with increased expression of NF-κB-related proteins in Kazakh patients with ESCC, suggesting that interaction between PLCE1 with the NF-κB signal pathway may be responsible for the carcinogenesis of ESCC, such as ESCC-related inflammation.

Duan X, Li X, Lou H, et al.
Genetic association of PLCE1, C11orf92-C11orf93, and NOC3L with colorectal cancer risk in the Han population.
Tumour Biol. 2014; 35(3):1813-7 [PubMed] Related Publications
Colorectal cancer (CRC) is a common malignant tumor that is influenced by an interaction between genetic and environmental factors. Currently, the inherited factors of CRC are unclear. Our study selected 19 tag single nucleotide polymorphisms (tSNPs) to investigate whether they were associated with CRC in the Han population. In this Han Chinese case-control study, we genotyped 203 CRC cases and 296 controls using Sequenom MassARRAY technology and analyzed their associations with CRC using χ(2) tests, SNPStats software, and SHEsis software. Based on χ(2) tests, PLCE1 -rs2077218, rs11187877 (p = 0.049) and C11orf92-C11orf93-rs3802842 (p = 0.023) correlate with CRC risk. In the genetic model analyses, we found the genotype "CC" of rs3802842 in C11orf92-C11orf93 may significantly increase CRC risk in the recessive model (p = 0.0071), whereas "GT" of rs17109928 in NOC3L may decrease the risk in the over-dominant model (p = 0.0091). Using SHEsis software, we found PLCE1 and NOC3L are strongly linked, and the "GCCATTCTGTC" haplotype may increase the risk of CRC (p = 0.049). We found three genes (PLCE1, C11orf92-C11orf93, and NOC3L) are associated with CRC susceptibility. In combination with previous reports, our results suggest that these genes may be associated with CRC in the Han population.

Cui X, Chen Y, Liu L, et al.
Heterozygote of PLCE1 rs2274223 increases susceptibility to human papillomavirus infection in patients with esophageal carcinoma among the Kazakh populations.
J Med Virol. 2014; 86(4):608-17 [PubMed] Related Publications
The involvement of human papillomavirus (HPV) in the carcinogenesis of esophageal squamous carcinoma remains undetermined. However, three genome-wide association studies of esophageal cancer have identified a shared susceptibility locus at 10q23 (rs2274223: A5780G) in phospholipase C epsilon 1 (PLCE1). The current study aims to present a comprehensive and novel spectrum about the HPV genotype distribution of esophageal carcinoma in Kazakhs and assess its association with PLCE1 polymorphisms. The HPV genotypes in 183 patients with esophageal cancer and 89 controls selected from the Kazakh population were evaluated using the HPV gene chip. The PLCE1 rs2274223 variant was genotyped in esophageal carcinoma patients by MALDI-ToF Mass Spectrometry. The presence of seven HPV genotypes in esophageal carcinoma tissues-including HPV 16, 18, 35, 52, 6, 11, 43-was significantly higher at 31.7% than those in controls at 9.0% (P < 0.001). Such presence was strongly associated with increased risk of esophageal carcinoma (OR 4.70; 95% CI 2.13-10.36). Among all HPV genotypes detected, HPV16 was the most common genotype identified (29.0%, OR 4.13; 95% CI 1.87-9.13), which is significantly associated with well-differentiated esophageal carcinoma (P = 0.037). HPV-positive patients were generally younger than HPV-negative patients (70.1% vs. 29.3%, P = 0.013). PLCE1 rs2274223 genotypes AG and AG/GG were significantly associated with HPV-positive patients with esophageal carcinoma (OR 2.05, 95% CI 1.03-4.08 and OR 1.98, 95% CI 1.02-3.84, respectively). These findings suggest that heterozygote of PLCE1 rs2274223 increases susceptibility to HPV infection in patients with esophageal carcinoma among the Kazakh populations.

Zhang X, Zhang Y, Gu D, et al.
Increased risk of developing digestive tract cancer in subjects carrying the PLCE1 rs2274223 A>G polymorphism: evidence from a meta-analysis.
PLoS One. 2013; 8(10):e76425 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To date, the association between phospholipase C epsilon 1 (PLCE1) rs2274223 A>G and risk of digestive tract cancer (DTC) remains inconclusive. To derive a more precise estimation of the association, we conducted a meta-analysis on all eligible case-control studies involving 8281 cases and 10,532 controls.
METHODS: A comprehensive search was conducted to identify all eligible studies of PLCE1 rs2274223 polymorphism and digestive tract cancer risk. The pooled odds ratio (OR) and the 95% confidence interval (95% CI) were calculated using a fixed or random effect model. Heterogeneity, publication bias, and sensitivity analysis were also explored.
RESULTS: Overall, the PLCE1 rs2274223 A>G polymorphism was associated with risk of DTC in all genetic models (GA vs. AA: OR = 1.21, 95% CI = 1.14-1.29, P<0.001; GG vs. AA: OR = 1.30, 95% CI = 1.06-1.60, P = 0.012; GG/GA vs. AA: OR = 1.20, 95% CI = 1.10-1.32, P<0.001; GG vs. GA/AA: OR = 1.21, 95% CI = 1.01-1.46, P = 0.040). The recessive model did not reach statistically significance when the P values were Bonferroni corrected to 0.0125. In the stratified analysis by cancer type, ethnicity, and source of controls, significantly increased risk was observed for esophagus cancer, Asians in three genetic models (heterozygote comparison, homozygote comparison and dominant model), population-based studies in all genetic models, and for gastric cancer in the heterozygote comparison and dominant model after Bonferroni correction. However, in the subsite of gastric cancer, no significant association was found either in cardia or non-cardia gastric cancer.
CONCLUSION: Our study indicated that PLCE1 rs2274223 A>G polymorphism was significantly associated with increased risk of DTC, especially among Asian populations. Due to some minor limitations, our findings should be confirmed in further studies.

Wadhwa R, Song S, Lee JS, et al.
Gastric cancer-molecular and clinical dimensions.
Nat Rev Clin Oncol. 2013; 10(11):643-55 [PubMed] Free Access to Full Article Related Publications
Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer.

González CA, Sala N, Rokkas T
Gastric cancer: epidemiologic aspects.
Helicobacter. 2013; 18 Suppl 1:34-8 [PubMed] Related Publications
A multifactorial and multistep model of gastric cancer (GC) is currently accepted, according to which different environmental and genetic factors are involved at different stages in the cancer process. The aim of this article is to review the most relevant information published on the relative contribution of genetic and environmental factors. Large meta-analyses confirmed the association between IL8, IL10, TNF-b, TP53 and PSCA, while genetic variation at different genes such as XPG, PLCE1, HFE, ERCC5, EZH2, DOC2, CYP19A1, ALDH2, and CDH1 have been reported to be associated with GC risk. Several microRNAs have also been associated with GC and their prognosis. Cohort studies have shown the association between GC and fruit, flavonoid, total antioxidant capacity, and green tea intake. Obesity was associated with cardia GC, heme iron intake from meat with GC risk. Several large meta-analyses have confirmed the positive association of GC with salt intake and pickled foods and the negative association with aspirin use.

Cui XB, Chen YZ, Pang XL, et al.
Multiple polymorphisms within the PLCE1 are associated with esophageal cancer via promoting the gene expression in a Chinese Kazakh population.
Gene. 2013; 530(2):315-22 [PubMed] Related Publications
Although recent genome-wide association studies of esophageal squamous cell carcinoma (ESCC) identified a susceptibility locus in phospholipase C epsilon 1 (PLCE1) in Chinese Han populations, few studies further confirmed these findings in pure Kazakh population in which there are higher incidence and mortality of ESCC. Here, we investigated the potential associations between 19 SNPs of PLCE1 and susceptibility to ESCC in 222 cases and 326 controls from a pure ethnic population of Kazakh. Real-time PCR and immunohistochemistry were performed to detect the PLCE1 expression levels and evaluate their association with PLCE1 polymorphism. We found that only 4 SNPs (rs753724, rs11187842, rs2274223, and rs12263737) with moderate linkage disequilibrium (LD) confer significantly increased risk of ESCC, with the ORs ranging from 1.43 to 2.04, and there was a risk allele dose-dependent increase in ESCC risk (P-trend=0.043). Especially, the risk effects of rs2274223 were more evident in poor differentiation and advanced clinical stages of Kazakh ESCC. Additionally, the significantly lowest PLCE1 mRNA expression was found in the KYSE-150 cell line having no risk alleles compared with other three cell lines having risk alleles, and the normal tissues of both homozygous mutant type of PLCE1 rs12263737 and rs2274223 had a higher PLCE1 staining score than that of homozygous wild type. Our findings suggested that genetic variants in PLCE1 might serve as candidate markers for Kazakh ESCC susceptibility, and these LD variants might influence ESCC risk individually and jointly by promoting the messenger RNA and protein expression of the gene.

Umar M, Upadhyay R, Mittal B
PLCE1 rs2274223 A>G polymorphism and cancer risk: a meta-analysis.
Tumour Biol. 2013; 34(6):3537-44 [PubMed] Related Publications
Phospholipase C epsilon 1 gene (PLCE1) encodes a phospholipase enzyme which regulates various physiological processes (cell growth, differentiation, and apoptosis) and is supposed to play a critical role in carcinogenesis. Recently, a single nucleotide polymorphism (rs2274223 A>G) in PLCE1 was reported as a novel susceptibility locus for esophageal and gastric cancers by genome-wide association studies performed in Chinese population. However, individual association studies replicating this finding showed inconclusive results. Therefore, we performed a meta-analysis of eligible studies to derive precise estimation of the association of PLCE1 rs2274223 A>G polymorphism with cancer risk. We performed pooled analysis of 12 case–control studies including 7,622 cases and 9,555 controls. Odds ratios and 95 % confidence interval were calculated to assess strength of association in overall studies and in subgroup analysis stratified by ethnicity, cancer types, and source of controls. All statistical analyses were performed by MIX 2.0 software. We found that PLCE1 rs2274223 A>G polymorphism was significantly associated with increased risk of cancer in log additive/dominant model and at allele level (GG vs. AA: OR = 1.24, 95 % CI = 1.01–1.53, P = 0.039; AG vs. AA: OR = 1.24, 95 % CI = 1.16–1.32, P < 0.001; AG + GG vs. AA: OR = 1.22, 95 % CI = 1.12–1.34, P < 0.001; and G vs. A allele: OR = 1.15, 95 % CI = 1.05–1.25, P = 0.002). Further, stratified analysis showed elevated risk of only gastric and esophageal tumors. Sub-group analysis based on ethnicity suggests PLCE1 polymorphism conferred significant risk among Asian (Chinese) but not in Caucasian. In conclusion, PLCE1 rs2274223 polymorphism may be used as potential biomarker for cancer susceptibility particularly for esophageal/gastric cancer and for the Chinese population.

Duan F, Xie W, Cui L, et al.
Novel functional variants locus in PLCE1 and susceptibility to esophageal squamous cell carcinoma: based on published genome-wide association studies in a central Chinese population.
Cancer Epidemiol. 2013; 37(5):647-52 [PubMed] Related Publications
A novel functional single nucleotide polymorphism (SNP) rs2274223 located in the phospholipase C epsilon 1 (PLCE1) gene was found to be associated with the risk of esophageal squamous cell carcinoma (ESCC) by three large-scale genome-wide association studies (GWAS) in Chinese populations. In the present study, we validated this finding and also explored the risk of ESCC associated with other two unreported potentially functional SNPs (rs17417407 G>T and rs2274224 C>G) of PLCE1 in a population-based case-control study to investigate the association between these three potentially functional SNPs in PLCE1 and susceptibility to ESCC. A total of 381 ESCC cases and 420 controls matched by age and sex were recruited and successfully genotyped for three SNPs (rs17417407, rs2274223 and rs2274224) of the PLCE1 in a central Chinese population. SNP rs2274223 was independently associated with increased risk of ESCC (adjusted odds ratio [OR], 2.80; 95% confidence interval [95% CI], 1.45-5.39 for GG vs. AA), and SNP rs2274224 was found to be associated with decreased risk of ESCC (adjusted OR, 0.65; 95% CI, 0.46-0.91 for CG vs. CC). The combined effects of risk alleles for three SNPs (rs17417407T, rs2274223G and rs2274224G) were found to be associated with elevated risk of ESCC in a dose-dependent effect manner (Ptrend=0.005). The Grs17417407Ars2274223Crs2274224 haplotype decreased the risk of ESCC (adjusted OR, 0.76; 95% CI, 0.62-0.93), meanwhile the Grs17417407Grs2274223Crs2274224 and Trs17417407Grs2274223Crs2274224 haplotypes could increase the risk of ESCC (adjusted OR, 1.75; 95% CI, 1.33-2.18 and OR, 2.51; 95% CI, 1.15-2.49). Gene-environment interaction analysis presented a best model consisted of four factors (rs2274223, rs2274224, family history, and smoking) with testing balance accuracy (TBA): 0.66 and cross validation consistency (CVC): 7/10, which could increase the esophageal cancer risk in the "high risk group" with 3.67-fold (OR: 3.67, 95% CI: 2.74-4.92), compared to the "low risk group". Our results further confirmed that genetic variations in PLCE1 may contribute to ESCC risk associated with tobacco exposure in a central Chinese population. Further functional studies are needed to validate our results.

Chen YZ, Cui XB, Hu JM, et al.
Overexpression of PLCE1 in Kazakh esophageal squamous cell carcinoma: implications in cancer metastasis and aggressiveness.
APMIS. 2013; 121(10):908-18 [PubMed] Related Publications
Three recent large-scale genome-wide association studies (GWAS) in Chinese Han populations have identified an esophageal squamous cell carcinoma (ESCC) susceptibility locus within phospholipase C epsilon 1 (PLCE1) gene, which encodes a phospholipase involved in intracellular signaling. The expressed PLCE1 in ESCC, however, are inconsistent. This study examined PLCE1 expression by immunohistochemistry (IHC) from 110 ethnic Kazakh ESCC patients and 50 from adjacent normal esophageal tissues (NETs). The expressed PLCE1 was localized in cytoplasm, especially in the peripheral layers of cancer cell nests, which was significantly higher in tumors than in NETs (p < 0.001). Increased expression of PLCE1 was correlated with advanced tumor-node-metastasis (TNM) stages (p = 0.015) and lymph node metastasis (p = 0.003) in patients with ESCC. Of the 110 patients, we examined 50 paired ESCC tissues and corresponding NETs by quantitative RT-PCR (polymerase chain reaction) and the mean mRNA level of PLCE1 in ESCC was 1.85-fold higher compared with those in corresponding NETs (p = 0.0012). Meanwhile, 4 of 5 ESCC cell lines also showed elevated expression of PLCE1 mRNA. Furthermore, elevated expression of PLCE1 mRNA in Kazakh ESCC was associated with its immunoreactivity (ρ = 0.297, p = 0.040), lymph node metastasis (p < 0.001), and advanced TNM stages of ESCC (p = 0.013). To our knowledge, this study demonstrates for the first time that PLCE1 overexpression correlates with lymph node metastasis and advanced TNM stages of Kazakh ESCC, implicating a role of PLCE1 in cancer metastasis and aggressiveness in ethnic Kazakh patients with ESCC. Furthermore, the current findings may warrant investigations into whether inhibiting PLCE1 could be a strategy for targeted anticancer therapy particularly for Kazakh ESCC.

Dura P, Bregitha CV, te Morsche RH, et al.
GWAS-uncovered SNPs in PLCE1 and RFT2 genes are not implicated in Dutch esophageal adenocarcinoma and squamous cell carcinoma etiology.
Eur J Cancer Prev. 2013; 22(5):417-9 [PubMed] Related Publications
Susceptibility to esophageal carcinoma (EC) is influenced by the interaction between genetic and environmental factors. To clarify the etiology of EC, several genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in PCLE1 and RFT2 genes as esophageal squamous cell carcinoma (ESCC) susceptibility loci in Asian populations. This study aimed to determine whether these SNPs also modify the risk of esophageal adenocarcinoma (EAC) and ESCC in western populations of Caucasian ethnicity. A European case-control study including 349 EC patients and 580 controls matched for age, sex, geographical location, and race was carried out. The SNPs rs2274223 in the PCLE1 gene at chromosome 10q23 and rs13042395 in the RFT2 gene at chromosome 20p13 were determined using PCR. Genotype distributions were compared between patients and controls, and odds ratios with 95% confidence intervals were calculated. The total EC group included 86 patients with ESCC and 258 patients with EAC. The distribution of PLCE1 and RFT2 genotypes did not differ between patients with EAC or ESSC, and the controls. In contrast to the modulation of the risk of ESCC in Asians, it is unlikely that the PLCE1 rs2274223 and RFT2 13042395 SNPs play a role in EAC or ESCC susceptibility in Dutch Caucasians.

Bye H, Prescott NJ, Lewis CM, et al.
Distinct genetic association at the PLCE1 locus with oesophageal squamous cell carcinoma in the South African population.
Carcinogenesis. 2012; 33(11):2155-61 [PubMed] Free Access to Full Article Related Publications
Oesophageal squamous cell carcinoma (OSCC) has a high prevalence in the Black and Mixed Ancestry populations of South Africa. Recently, three genome-wide association studies in Chinese populations identified five new OSCC susceptibility loci, including variants at PLCE1, C20orf54, PDE4D, RUNX1 and UNC5CL, but their contribution to disease risk in other populations is unknown. In this study, we report testing variants from these five loci for association with OSCC in the South African Black (407 cases and 849 controls) and Mixed Ancestry (257 cases and 860 controls) populations. The RUNX1 variant rs2014300, which reduced risk in the Chinese population, was associated with an increased risk of OSCC in the Mixed Ancestry population [odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.09-1.63, P = 0.0055], and none of the five loci were associated in the Black population. Since PLCE1 variants increased the risk of OSCC in all three Chinese studies, this gene was investigated further by sequencing in 46 Black South Africans. This revealed 48 variants, 10 of which resulted in amino acid substitutions, and much lower linkage disequilibrium across the PLCE1 locus than in the Chinese population. We genotyped five PLCE1 variants in cases and controls, and found association of Arg548Leu (rs17417407) with a reduced risk of OSCC (OR = 0.74, 95% CI = 0.60-0.93, P = 0.008) in the Black population. These findings indicate several differences in the genetic contribution to OSCC between the South African and Chinese populations that may be related to differences in their genetic architecture.

Yuan LJ, Jin TB, Yin JK, et al.
Polymorphisms of tumor-related genes IL-10, PSCA, MTRR and NOC3L are associated with the risk of gastric cancer in the Chinese Han population.
Cancer Epidemiol. 2012; 36(6):e366-72 [PubMed] Related Publications
BACKGROUND: Gastric cancer is the fourth most common cancer in the world. Environmental and genetic factors both play critical roles in the etiology of gastric cancer. Hundreds of SNPs have been identified to have association with the risk of gastric cancer in many races. In this study, 25 SNPs in genes for IL-10, IL-1B, MTRR, TNF-а, PSCA, PLCE1 and NOC3L were analyzed to further evaluate their associations with gastric cancer susceptibility in the Chinese Han population.
METHODS: Two hundred and seventy nine gastric cancer patients and 296 healthy controls were recruited in this study. SNP genotyping was conducted using Sequenom MassARRAY RS1000. Data management and statistical analyses were conducted by Sequenom Typer 4.0 Software and Pearson's χ(2) test.
RESULTS: One protective allele and three risk alleles for gastric cancer patients were found in this study. The allele "G" of rs1801394 in MTRR showed an association with a decreased risk of gastric cancer: odds ratio (OR) = 0.74, 95% confidence interval (95% CI) = 0.57-0.97, P = 0.030 in the additive model; OR = 0.495, 95% CI = 0.26-0.95, P = 0.034 in the recessive model. The other three SNPs, the allele "C" of rs1800871 in IL10 (OR = 1.33, 95% CI = 1.04-1.90; P = 0.026 in the additive model; OR = 1.46, 95% CI = 1.04-2.06; P = 0.030 in the recessive model), the allele "A" of rs2976391 in PSCA (OR = 1.30, 95% CI = 1.01-1.66; P = 0.041 in the additive model and OR = 1.48, 95% CI = 1.04-2.11, P = 0.028 in the recessive model), and the allele "G" of rs17109928 in NOC3L gene (OR = 1.34, 95% CI = 1.01-1.78; P = 0.042 by additive model analysis; OR = 1.47, 95% CI = 1.04-2.07, P = 0.028 by dominant model analysis), showed an association with an increased risk of gastric cancer.
CONCLUSIONS: These results indicate the importance of four gastric cancer susceptibility polymorphisms of IL-10, NOC3L, PSCA and MTRR in the Chinese Han population, which could be used in the determination of gastric cancer risk in clinical practice.

Gu H, Ding G, Zhang W, et al.
Replication study of PLCE1 and C20orf54 polymorphism and risk of esophageal cancer in a Chinese population.
Mol Biol Rep. 2012; 39(9):9105-11 [PubMed] Related Publications
Esophageal cancer is one of the most aggressive cancers in the world. Recent large-scale genome-wide association studies (GWAS) reported that functional genetic variations in the phospholipase C epsilon gene (PLCE1) were strongly associated with risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in Chinese population. For C20orf54 rs13042395 genotype and risk of esophageal cancer, the results were inconsistent. We conducted a replication case-control study to evaluate the genetic effects of these two functional single nucleotide polymorphisms (SNPs) on the development of esophageal cancer. A total of 380 cases and 380 controls were recruited for this study. The genotypes were determined by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF MS). The variant alleles of the functional polymorphism, PLCE1 rs2274223 SNP was associated with the increased risk of esophageal cancer [adjusted odds ratio (OR) = 1.95, 95 % confidence interval (CI) = 1.05-3.59 for PLCE1 rs2274223 GG vs. AA]. However, there was no significant association between the C20orf54 rs13042395 genotype and esophageal cancer risk (adjusted OR = 0.99, 95 % CI = 0.63-1.57 for C20orf54 rs13042395 TT vs. CC). Stratified analyses indicated a significantly increased risk of esophageal cancer associated with the PLCE1 rs2274223 AG genotype was more evident among females, younger patients and never drinkers, compared with the PLCE1 rs2274223 AA genotypes. Stratified analyses also indicated a significantly increased risk of esophageal cancer associated with the PLCE1 rs2274223 GG genotype was more evident among never smokers and never drinkers compared with the PLCE1 rs2274223 AA genotypes. These findings indicated that functional polymorphisms PLCE1 rs2274223 might contribute to esophageal cancer susceptibility.

Hu H, Yang J, Sun Y, et al.
Putatively functional PLCE1 variants and susceptibility to esophageal squamous cell carcinoma (ESCC): a case-control study in eastern Chinese populations.
Ann Surg Oncol. 2012; 19(7):2403-10 [PubMed] Related Publications
BACKGROUND: A novel variant rs2274223 located in the phospholipase C epsilon 1 (PLCE1) gene was found to be associated with risk of esophageal squamous cell carcinoma (ESCC) by 2 large-scale genome-wide association studies (GWASs) in Chinese populations. In this study, we aimed to assess such an association in an eastern Chinese population and to address its possibly functional role in the etiology of ESCC.
METHODS: A total of 1061 ESCC cases and 1211 controls were recruited and successfully genotyped for 2 single nucleotide polymorphisms (SNPs) (rs2274223 and rs11187870) of the PLCE1 gene by the TaqMan assay. Real-time PCR and immunohistochemical (IHC) analysis were applied to assess mRNA and protein expression levels, respectively, in a subset of tumor samples.
RESULTS: SNP rs2274223 was independently associated with risk of ESCC (adjusted odds ratio [OR], 1.49; 95% confidence interval [95% CI], 1.03-2.17 for GG vs AA), and SNP rs11187870 was also found to be associated with risk of ESCC assuming a dominant model (adjusted OR, 1.20; 95% CI, 1.00-1.44 for CG/CC vs GG). The Grs2274223Crs11187870 haplotype increased the risk for ESCC by 1.22-fold (95% CI, 1.04-1.42). Further experiments showed that overall PLCE1 mRNA expression was lower in tumor than in paired normal tissues (0.067±0.016 vs 0.264±0.067, P<.05), and the IHC analysis showed the normal tissues of rs2274223 GG genotype had a lower PLCE1 staining score than that of the AG genotype (0.40±0.22 vs 1.33±0.32, P<.05).
CONCLUSIONS: PLCE1 SNP rs2274223 A>G change may reduce gene expression, and the variant G genotypes might contribute to risk of ESCC.

Danielsen SA, Cekaite L, Ågesen TH, et al.
Phospholipase C isozymes are deregulated in colorectal cancer--insights gained from gene set enrichment analysis of the transcriptome.
PLoS One. 2011; 6(9):e24419 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is one of the most common cancer types in developed countries. To identify molecular networks and biological processes that are deregulated in CRC compared to normal colonic mucosa, we applied Gene Set Enrichment Analysis to two independent transcriptome datasets, including a total of 137 CRC and ten normal colonic mucosa samples. Eighty-two gene sets as described by the Kyoto Encyclopedia of Genes and Genomes database had significantly altered gene expression in both datasets. These included networks associated with cell division, DNA maintenance, and metabolism. Among signaling pathways with known changes in key genes, the "Phosphatidylinositol signaling network", comprising part of the PI3K pathway, was found deregulated. The downregulated genes in this pathway included several members of the Phospholipase C protein family, and the reduced expression of two of these, PLCD1 and PLCE1, were successfully validated in CRC biopsies (n = 70) and cell lines (n = 19) by quantitative analyses. The repression of both genes was found associated with KRAS mutations (P = 0.005 and 0.006, respectively), and we observed that microsatellite stable carcinomas with reduced PLCD1 expression more frequently had TP53 mutations (P = 0.002). Promoter methylation analyses of PLCD1 and PLCE1 performed in cell lines and tumor biopsies revealed that methylation of PLCD1 can contribute to reduced expression in 40% of the microsatellite instable carcinomas. In conclusion, we have identified significantly deregulated pathways in CRC, and validated repression of PLCD1 and PLCE1 expression. This illustrates that the GSEA approach may guide discovery of novel biomarkers in cancer.

Ma H, Wang LE, Liu Z, et al.
Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck.
BMC Cancer. 2011; 11:258 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN. Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN.
METHODS: We genotyped three potentially functional SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) of PLCE1 in 1,098 SCCHN patients and 1,090 controls matched by age and sex in a non-Hispanic white population.
RESULTS: Although none of three SNPs was alone significantly associated with overall risk of SCCHN, their combined effects of risk alleles (rs2274223G, rs3203713G and rs11599672G) were found to be associated with risk of SCCHN in a locus-dose effect manner (Ptrend=0.046), particularly for non-oropharyngeal tumors (Ptrend=0.017); specifically, rs2274223 was associated with a significantly increased risk (AG vs. AA: adjusted OR=1.29, 95% CI=1.01-1.64; AG/GG vs. AA: adjusted OR=1.30, 95% CI=1.03-1.64), while rs11599672 was associated with a significantly decreased risk (GG vs. TT: adjusted OR=0.54, 95% CI=0.34-0.86; TG/GG vs. TT: adjusted OR=0.76, 95% CI=0.61-0.95).
CONCLUSIONS: Our findings suggest that PLCE1 variants may have an effect on risk of SCCHN associated with tobacco and alcohol exposure, particularly for those tumors arising at non-oropharyngeal sites. These findings, although need to be validated by larger studies, are consistent with those in esophageal and gastric cancers.

Abnet CC, Freedman ND, Hu N, et al.
A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma.
Nat Genet. 2010; 42(9):764-7 [PubMed] Free Access to Full Article Related Publications
We conducted a genome-wide association study of gastric cancer and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 SNPs. We report a combined analysis of 2,240 gastric cancer cases, 2,115 ESCC cases and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex and study, multiple variants at 10q23 had genome-wide significance for gastric cancer and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for gastric cancer (P = 8.40 x 10(-9); per-allele odds ratio (OR) = 1.31) and ESCC (P = 3.85 x 10(-9); OR = 1.34). The association with gastric cancer differed by anatomic subsite. For tumors in the cardia the association was stronger (P = 4.19 x 10(-15); OR = 1.57), and for those in the noncardia stomach it was absent (P = 0.44; OR = 1.05). Our findings at 10q23 could provide insight into the high incidence of both cancers in China.

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