<scp>LAPTM</scp>4B gene polymorphism augments the risk of cancer: Evidence from an updated meta‐analysis

Lysosome-associated protein transmembrane-4 beta (LAPTM4B) has two alleles named as LAPTM4B*1 and LAPTM4B*2 (GenBank No. AY219176 and AY219177). Allele *1 has a single copy of a 19-bp sequence in the 5` untranslated region (5`UTR), but allele *2 contains tandem repeats of 19-bp sequence.1 LAPTM4B gene is located on long chromosome 8 (8q22.1) and contains seven exons that encodes two isoforms of tetratransmembrane proteins, LAPTM4B-24 and LAPTM4B-35, with molecular weights of 25 kDa and 35 kDa respectively. The LAPTM4B-35′s primary structure is formed by 317 amino acid residues, and LAPTM4B-24 comprised 226 amino acids. LAPTM4B, an integral membrane protein, contains several lysosomal-targeting motifs at the C terminus and colocalizes with late endosomal and lysosomal markers. LAPTM4B is a proto-oncogene, which becomes up-regulated in various cancers. Preceding studies have examined the possible link between LAPTM4B polymorphism and susceptibility to several cancers,1-26 but the findings are still inconsistent. Hence, the present meta-analysis was designed to investigate the impact of LAPTM4B polymorphism on risk of cancer. A comprehensive search in Web of Science, PubMed, Scopus, and Google Scholar databases was done for all articles describing an association between LAPTM4B polymorphism and cancer risk published up to April 2018. The search strategy was “cancer, carcinoma, tumor, neoplasms,” “LAPTM4B, Lysosome-associated protein transmembrane-4,” and “polymorphism, mutation, variant.” Relevant studies included the meta-analysis if they met the following inclusion criteria: (a) Original case-control studies that evaluated the LAPTM4B polymorphism and the risk of cancer; (b) studies provided sufficient information of the genotype frequencies of LAPTM4B polymorphism in both cases and controls. The exclusion criteria were: (a) conference abstract, case reports, reviews, duplication data; (b) insufficient genotype information provided. Data extraction was done by two independently authors. From each study, the following data were collected: the first author's name, publication year, country, ethnicity of participants, cancer type, genotyping methods of LAPTM4B polymorphism, the sample size, and the genotype and allele frequencies of cases and controls (Table 1). Meta-analysis was carried out using Revman 5.3 software (Copenhagen: The Cochrane Collaboration, 2014, The Nordic Cochrane Centre) and stata 14.1 software (Stata Corporation, College Station, TX, USA). For each study, Hardy-Weinberg equilibrium (HWE) was determined by the chi-squared test, in order to verify the representativeness of the study population. The association between LAPTM4B polymorphism in relation to cancer risk was evaluated by pooled odds ratios (ORs) and their 95% confidence intervals (CIs). Pooled ORs and their 95% CIs for codominant, dominant, recessive, overdominant and the allelic comparison genetic inheritance models were calculated. The significance of the pooled OR was assessed by the Z test, and P < 0.05 was considered statistically significant. The choice of using fixed or random effects model was determined by the results of the between-study heterogeneity test, which was measured using the Q test and I2 statistic. If the test result was I2 ≥ 50% or PQ < 0.1, indicating the presence of heterogeneity, the random effect model was selected; otherwise, the fixed-effects model was chosen. The funnel plot was used to estimate the publication bias. The degree of asymmetry was measured using Egger's test; P < 0.05 was considered significant publication bias. To measure the potential influence of each study on the overall effect size, sensitivity analysis was performed. The characteristics and relevant data of the included studies are shown in Table 1. The results of the meta-analysis revealed a significant association between LAPTM4B polymorphism and cancer susceptibility cancer in codominant (OR = 1.42, 95% CI = 1.27-1.59, P < 0.00001, *1/2 vs *1/1; OR = 2.01, 95% CI = 1.69-2.39, P < 0.00001, *2/2 vs *1/1), dominant (OR = 1.50, 95% CI = 1.34-1.69, P < 0.00001, *1/2 + *2/2 vs *1/1), recessive (OR = 1.73, 95% CI = 1.53-1.95, P < 0.00001, *2/2 vs *1/1 + *1/2), overdominant (OR = 1.28, 95% CI = 1.17-1.41, P < 0.00001, *1/2 vs *1/1 + *2/2), and allele (OR = 1.40, 95% CI = 1.28-1.53, P < 0.00001, *2 vs *1) inheritance model tested (Figure 1). Stratifying according to cancer types proposed that LAPTM4B polymorphism significantly increased the risk of breast cancer, gastrointestinal cancer, gynaecological cancer, liver cancer, lung cancer, and lymphoma (data not shown). The potential publication bias was evaluated using a Begg's funnel plot and Egger's test and the analysis suggested no publication bias for this meta-analysis of the heterozygous codominant, dominant, recessive, overdominanat, and allele model (all P-values for bias >0.05). We executed sensitivity analysis by neglecting a single study each time to reflect the influence of the individual data set to the pooled OR. The results indicated that the significance of pooled ORs for LAPTM4B polymorphism was not extremely influenced, suggesting the stability and reliability of the results in this meta-analysis. In the current study, we performed a meta-analysis to find out the exact role of LAPTM4B polymorphism on risk of cancer. The results revealed that LAPTM4B polymorphism significantly increased the risk of cancer in codominant, dominant, overdominant, and allele genetic inheritance models. Stratification by cancer types suggested that LAPTM4B polymorphism is associated with the risk of breast cancer, gynaecological cancer, gastrointestinal cancer, liver cancer, lung cancer, and lymphoma. LAPTM4B is a proto-oncogene that is overexpressed in various types of cancers. It has been proposed that overexpression of LAPTM4B-35 promote proliferation, invasion, and migration. Its up-regulation might be caused by gene amplification as well as transcriptional up-regulation. LAPTM4B alleles have the same sequence except for one 19-bp fragment for LAPTM4B *1 and two tight tandem fragments for LAPTM4B *2 in the 5′UTR of exon 1.23 The 19-bp alteration in 5′UTR of the first exon of the LAPTM4B gene can shift the open reading frame (ORF), resulting in two alternate protein isoforms, LAPTM4B-35 and LAPTM4B-40. In conclusion, the finding of this meta-analysis illustrated that LAPTM4B polymorphism may affect the risk of development of cancers. SG was supported by the operating grant from CHRIM, general operating grant from Health Science Foundation, and Research Manitoba New Investigator operating grant. MJŁ acknowledges the support from NCN grant #: 2016/21/B/NZ1/02812, by LE STUDIUM Institute for Advanced Studies (region Centre-Val de Loire, France) through its Smart Loire Valley General Program, cofunded by the Marie Skłodowska-Curie Actions, grant #: 665790. The authors declare no competing of interests.

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