Distinct genetic association at the PLCE1 locus with oesophageal squamous cell carcinoma in the South African population

Department of Medical and Molecular Genetics, King's College London, King's Health Partners, Guy's Hospital, London, United Kingdom.
Carcinogenesis (Impact Factor: 5.33). 08/2012; 33(11). DOI: 10.1093/carcin/bgs262
Source: PubMed


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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    • "Additional studies confirming the associated locus in other populations are essential to our understanding of the pathogenesis of ESCC and GCA. Several studies characterized and replicated the PLCE1 rs2274223 alteration in South Africa, Caucasian and Asian population for ESCC and GCA after GWAS [15–21]. But the results were generally inconsistent and inconclusive, probably due to the small size in each study. "
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    ABSTRACT: Two recent genome-wide association studies have identified a shared susceptibility variation PLCE1 rs2274223 for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinomas (GCA). Subsequent case-control studies have reported this association in other populations. However, the findings were controversial and the effect remains undetermined. Our aim is to provide a precise quantification of the association between PLCE1 rs2274223 variation and the risk of ESCC and GCA. Studies were identified by a literature search in MEDLINE and EMBASE databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association in allele, dominant, recessive, homozygous, and heterozygous models. Ten articles were identified, including 22156 ESCC cases and 28803 controls, 5197 GCA cases and 17613 controls. Overall, PLCE1 rs2274223 G allele (G vs. A: OR=1.26, 95% CI: 1.15-1.39 for ESCC; OR=1.51, 95% CI: 1.35-1.69 for GCA) and its carrier (GG +AG vs. AA: OR = 1.23; 95% CI =1.02-1.49 for ESCC; OR =1.62; 95% CI =1.15-2.29 for GCA) were significantly associated with the risk of ESCC and GCA. In stratified analysis by ethnicity, significant association of PLCE1 rs2274223 G allele and the risk of ESCC (OR=1.33, 95% CI 1.21-1.45) and GCA (OR =1.56, 95% CI: 1.47-1.64) was observed in Chinese population. Our meta-analysis results indicated that PLCE1 rs2274223 G allele significantly contributed to the risk of ESCC and GCA, especially in Chinese population.
    PLoS ONE 07/2013; 8(7):e69214. DOI:10.1371/journal.pone.0069214 · 3.23 Impact Factor
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    • "The combined search yielded 93 references. The study selection process is shown in Figure 1.A total of thirteen studies from nine articles were ultimately included; this resulted in the examination of 10,353 patients and 13,902 controls [16–19,27–31]. Eight studies were available for ESCC, and this included a total of 5,226 cases and 8,111 controls. "
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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 · 3.23 Impact Factor
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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 · 1.72 Impact Factor
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