Distinct genetic association at the PLCE1 locus with oesophageal squamous cell carcinoma in the South African population.
ABSTRACT 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.
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ABSTRACT: Phospholipase C epsilon 1 (PLCE1) plays crucial roles in carcinogenesis and progression of several cancers. A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus. To evaluate the role of the Phospholipase C epsilon 1 (PLCE1) polymorphism in cancer susceptibility. We performed a meta-analysis of all available studies, including 8,689 cases and 10,794 controls to derive a more precise relationship. An odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the association between PLCE1 rs2274223 polymorphism and cancer risk. A total of 14 case-control studies were included in the present meta-analysis. Overall significant associations were observed (AG vs. AA: OR=1.17, 95%CI=1.04-1.31; GG vs. AA: OR=1.32, 95%CI=1.06-1.66; AG/GG vs. AA: OR=1.19, 95%CI=1.05-1.34; G vs. A: OR=1.16, 95%CI=1.04-1.29) in all cancer types. In the subgroup analysis, PLCE1 rs2274223 polymorphism was significantly increased risk of cancer in Chinese population by ethnicity and upper aerodigestive tract cancer by cancer types. Our meta-analysis suggested the PLCE1 rs2274223 might act as a cancer risk factor among all subjects, especially in the Chinese population and upper aerodigestive tract cancer.Cancer biomarkers: section A of Disease markers 01/2013; 13(6):483-9. DOI:10.3233/CBM-130388 · 1.19 Impact Factor
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ABSTRACT: In recent years, the PLCE1 rs2274223 polymorphism has been extensively investigated as a potential risk factor for upper gastrointestinal cancers, including squamous cell carcinoma (ESCC) and gastric cancer. However, the results of these studies have been inconsistent. A meta-analysis of 13 case-control studies was performed including more than 11,000 subjects with genotyped PLCE1 rs2274223 polymorphisms. Odds ratios (OR) with 95% confidence intervals (CI) were employed to assess the association of the PLCE1 rs2274223 polymorphism with a susceptibility to ESCC or gastric cancer. A statistically significant increase in the risk of ESCC was associated with the PLCE1 rs2274223 polymorphism. This included the homozygous genetic model (OR = 1.46), heterozygous genetic model (OR = 1.25) and allelic genetic model (OR = 1.23). Similar results were consistently found for gastric cancer. In a subgroup analysis, the PLCE1 rs2274223 polymorphism was found to be a very sensitive marker for gastric cardia cancer as shown by the homozygous genetic model (OR = 2.23), heterozygous genetic model(OR = 1.59) and allelic genetic model (OR = 1.47). The risk associations of all of the gastric cardia cancer models were statistically significant. In contrast, none of the genetic models for non-cardia gastric cancer were significant. In this meta-analysis, the PLCE1 rs2274223 polymorphism was confirmed to have a statistically significant association with an increasing risk of ESCC and gastric cancer. The increase risk was especially observed for gastric cardia cancer.PLoS ONE 06/2013; 8(6):e67229. DOI:10.1371/journal.pone.0067229 · 3.53 Impact Factor
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ABSTRACT: 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.Tumor Biology 06/2013; 34(6). DOI:10.1007/s13277-013-0932-7 · 2.84 Impact Factor