# Correlation of DEPDC5 rs1012068 and rs5998152 Polymorphisms with Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Authors: Shaoliang Zhu; Zhenyong Tang; Mengjie Zou; Tingting Tan; Yi Tang; Yuanyuan Chen; Bin Liang; Dongyi Xie; Yongyu Yang; Shaowei Xie; Guangyuan Xie; Xiaofeng Dong; Tianqi Liu; Yuntian Tang; Jianrong Yang
Journal: Journal of Oncology
 (2023)

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## Abstract

Background. Emerging evidence has shown that two common genetic polymorphisms within the pleckstrin domain-containing protein 5 (DEPDC5), rs1012068 and rs5998152, may be associated with the risk of hepatocellular carcinoma (HCC), especially in those individuals chronically infected with the hepatitis C virus (HCV) or the hepatitis B virus (HBV). However, these findings have not been consistently replicated in the literature due to limited sample sizes or different etiologies of HCC. Thus, the present systematic review and meta-analysis were performed to resolve this inconsistency. Methods. The databases PubMed, Embase, Web of Science, the China National Knowledge Infrastructure, and Scopus were searched up to December 12, 2022. Data from relevant studies were pooled, and odds ratios and 95% confidence intervals were calculated. Results. A total of 11 case-control studies encompassing 2,609 cases and 8,171 controls on rs1012068 and three encompassing 411 cases and 1,448 controls on rs5998152 were included. Results indicated that the DEPDC5 rs1012068 polymorphism did not significantly increase HCC risk in the total population (allelic model (OR = 1.32, 95% CI = 1.04–1.67, P = 0.02); the recessive model (OR = 1.42, 95% CI = 0.96–2.10, P = 0.08); the dominant model (OR = 1.43, 95% CI = 1.09–1.87, P = 0.01); the homozygous model (OR = 1.61, 95% CI = 1.01–2.57, P = 0.05); the heterozygous model (OR = 1.39, 95% CI = 1.09–1.79, P = 0.009)). Subgroup analyses based on ethnicity and etiology revealed that the rs1012068 polymorphism, under all five genetic models, was associated with increased HCC risk in Asians or in individuals with chronic HBV infection but not in individuals with chronic HCV infection. A significant association was also observed between rs5998152 and HCV-related HCC risk in Asians chronically infected with HCV under allelic, dominant, and heterozygous models. Conclusion. Our study suggests that the DEPDC5 rs1012068 polymorphism increases HCC risk, especially in Asians with chronic HBV infection, while the rs5998152 polymorphism increases HCC risk in Asians with chronic HCV infection.


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## Body

## 1. Introduction

Liver cancer is the fifth most common cancer and the fourth leading cause of cancer-related death worldwide. Among men, it is the fourth most frequent cancer and the second leading cause of cancer-related deaths [1]. Hepatocellular carcinoma (HCC) accounts for 75%–85% of cases of primary liver cancer worldwide [2]. The main risk factors for HCC are chronic infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV), aflatoxin-contaminated foods, heavy alcohol intake, excess body weight, type 2 diabetes, and smoking. Besides these etiological factors, increasing evidence has revealed that host genetic variations, including single-nucleotide polymorphisms (SNPs), might also play a role in HCC development and progression.Pleckstrin domain-containing protein 5 (DEPDC5) has been implicated in focal epilepsy, brain malformation, and sudden unexplained death in epilepsy [3–5]. DEPDC5 may be a target to treat epilepsy because it negatively regulates amino acid sensing through the signaling pathway involving the mammalian target of rapamycin complex 1 (mTORC1) [6, 7]. DEPDC5 also negatively regulates the AKT-mTORC1 pathway, so its agonists may be useful against the activation of latent HIV-1 infection [8]. DEPDC5 may participate in a signaling pathway in which Pim1 and Akt act via mTORC1 to promote the proliferation and survival of cancer cells [9]. Downregulation of DEPDC5 leads to upregulation of matrix metalloprotease 2 through the β-catenin pathway, which may contribute to HCV-related fibrosis [10]. Such downregulation also renders HCC tumors more resistant to reactive oxygen species under the leucine-depleted conditions of chronic liver disease, contributing to poor patient outcomes [11].In addition to these associations between DEPDC5 and various diseases, polymorphisms in the DEPDC5 gene have been linked to the risk of HCC [12–23]. A genome-wide association study first demonstrated that the DEPDC5 variant rs1012068 could increase HCC risk in individuals with chronic HCV infection [12], and this relationship was replicated in several studies [15, 18, 20]. On the other hand, several studies did not find such a relationship [9, 14, 18]. Similarly, some studies found a significant association between rs1012068 and the risk of HBV-related HCC [13, 16], while another study failed to detect this relationship [14].These contradictory results may reflect the relatively small samples in individual studies, heterogeneity among control populations, and different HCC etiologies. We conducted the present systematic review and meta-analysis to clarify the relationship of DEPDC5 polymorphisms rs1012068 and rs5998152 with HCC risk. We also performed subgroup analyses based on ethnicity and the etiology of HCC.


## 2. Materials and Methods

### 2.1. Search Strategy

This meta-analysis complied with “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines [24]. A comprehensive search for relevant studies was performed in the PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, and Scopus databases from their inception through December 12, 2022. The following terms were used: “genetic polymorphism” or “single-nucleotide polymorphism” or “polymorphism” or “SNP” or “mutation” or “variation” or “variant,” or “liver tumor” or “liver cancer” or “hepatocellular carcinoma” or “liver neoplasms,” and “DEP domain containing 5” or “DEPDC5” or “rs1012068” or “rs5998152.” There were no language restrictions. Additional studies were identified through manual searching of references in original or review articles on this topic. If there was a duplication of published literature by the same research group, the study with the larger sample was selected. Any disagreements were resolved by discussion.


### 2.2. Inclusion and Exclusion Criteria

#### 2.2.1. Inclusion Criteria

(a)
The study cohorts included DEPDC5 rs1012068 and rs5998152 polymorphisms in patients with HCC(b)
Histological features were assessed by liver biopsy, and diagnostic criteria were clearly stated(c)
Unrelated case-control studies were included(d)
If two (or more) studies included the same cohort, only the most recent was included(e)
Sufficient data for estimating odds ratios (ORs) and 95% confidence intervals (CIs) on the HCC risk were reported or could be calculated


#### 2.2.2. Exclusion Criteria

(a)
The source of cases was unclear(b)
No clear diagnostic criteria for HCC were described(c)
The study was a duplicate publication(d)
The study was a review, meta-analysis, comment, or conference abstract(e)
Genotyping data were not reported in sufficient detail


### 2.3. Data Extraction

The data from the included studies were extracted by two independent investigators. Discrepancies during data extraction were resolved by a third investigator. The extracted information included the first author’s surname, publication year, country in which the study was conducted, ethnicity, cohort characteristics of the cases and controls, the total number of patients in the case and control groups, the number of subjects with each genotype, and matched parameters between cases and controls.


### 2.4. Assessment of Methodological Quality

Quality assessments of the eligible studies were performed using the Newcastle–Ottawa Scale (NOS) [25]. The NOS involves a total of 9 items, each of which has a score that ranges from 1 to 9. A NOS score of 5 points or above would be classified as a high-quality study, while a NOS score of 4 points or below would be classified as a poor-quality study [26].


### 2.5. Statistical Analysis

The unadjusted odds ratio (OR) and 95% confidence interval (CI) were used to assess the correlation of DEPDC5 rs1012068 and rs5998152 polymorphisms with the risk of HCC based on the genotype frequencies in cases and controls. The Z test was used to evaluate the significance of the association, withP < 0.05 considered significant. When P > 0.10 for the Q test, meta-analysis was performed using a fixed-effect model, indicating the absence of heterogeneity among studies; otherwise, a random-effect model was used. Review Manager 5.3 (Cochrane Collaboration) was used for all statistical tests for meta-analyses. Begg’s funnel plot and Egger’s linear regression in Stata 12.0 software (Stata Corp., College Station, TX, USA) were used to evaluate publication bias, with P < 0.05 considered significant.


## 2.1. Search Strategy

This meta-analysis complied with “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines [24]. A comprehensive search for relevant studies was performed in the PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, and Scopus databases from their inception through December 12, 2022. The following terms were used: “genetic polymorphism” or “single-nucleotide polymorphism” or “polymorphism” or “SNP” or “mutation” or “variation” or “variant,” or “liver tumor” or “liver cancer” or “hepatocellular carcinoma” or “liver neoplasms,” and “DEP domain containing 5” or “DEPDC5” or “rs1012068” or “rs5998152.” There were no language restrictions. Additional studies were identified through manual searching of references in original or review articles on this topic. If there was a duplication of published literature by the same research group, the study with the larger sample was selected. Any disagreements were resolved by discussion.


## 2.2. Inclusion and Exclusion Criteria

### 2.2.1. Inclusion Criteria

(a)
The study cohorts included DEPDC5 rs1012068 and rs5998152 polymorphisms in patients with HCC(b)
Histological features were assessed by liver biopsy, and diagnostic criteria were clearly stated(c)
Unrelated case-control studies were included(d)
If two (or more) studies included the same cohort, only the most recent was included(e)
Sufficient data for estimating odds ratios (ORs) and 95% confidence intervals (CIs) on the HCC risk were reported or could be calculated


### 2.2.2. Exclusion Criteria

(a)
The source of cases was unclear(b)
No clear diagnostic criteria for HCC were described(c)
The study was a duplicate publication(d)
The study was a review, meta-analysis, comment, or conference abstract(e)
Genotyping data were not reported in sufficient detail


## 2.2.1. Inclusion Criteria

(a)
The study cohorts included DEPDC5 rs1012068 and rs5998152 polymorphisms in patients with HCC(b)
Histological features were assessed by liver biopsy, and diagnostic criteria were clearly stated(c)
Unrelated case-control studies were included(d)
If two (or more) studies included the same cohort, only the most recent was included(e)
Sufficient data for estimating odds ratios (ORs) and 95% confidence intervals (CIs) on the HCC risk were reported or could be calculated


## 2.2.2. Exclusion Criteria

(a)
The source of cases was unclear(b)
No clear diagnostic criteria for HCC were described(c)
The study was a duplicate publication(d)
The study was a review, meta-analysis, comment, or conference abstract(e)
Genotyping data were not reported in sufficient detail


## 2.3. Data Extraction

The data from the included studies were extracted by two independent investigators. Discrepancies during data extraction were resolved by a third investigator. The extracted information included the first author’s surname, publication year, country in which the study was conducted, ethnicity, cohort characteristics of the cases and controls, the total number of patients in the case and control groups, the number of subjects with each genotype, and matched parameters between cases and controls.


## 2.4. Assessment of Methodological Quality

Quality assessments of the eligible studies were performed using the Newcastle–Ottawa Scale (NOS) [25]. The NOS involves a total of 9 items, each of which has a score that ranges from 1 to 9. A NOS score of 5 points or above would be classified as a high-quality study, while a NOS score of 4 points or below would be classified as a poor-quality study [26].


## 2.5. Statistical Analysis

The unadjusted odds ratio (OR) and 95% confidence interval (CI) were used to assess the correlation of DEPDC5 rs1012068 and rs5998152 polymorphisms with the risk of HCC based on the genotype frequencies in cases and controls. The Z test was used to evaluate the significance of the association, withP < 0.05 considered significant. When P > 0.10 for the Q test, meta-analysis was performed using a fixed-effect model, indicating the absence of heterogeneity among studies; otherwise, a random-effect model was used. Review Manager 5.3 (Cochrane Collaboration) was used for all statistical tests for meta-analyses. Begg’s funnel plot and Egger’s linear regression in Stata 12.0 software (Stata Corp., College Station, TX, USA) were used to evaluate publication bias, with P < 0.05 considered significant.


## 3. Results

### 3.1. Characteristics of Primary Studies

The flowchart of study selection is summarized in Figure1, and search strategies for each database are presented in Table S1. After a comprehensive search of the databases using the search strategies in Table S1, 54 relevant studies were compliant with the search strategy, of which 28 were excluded due to being duplicates. Another 11 were omitted after screening titles and abstracts. Among the 15 studies remaining, one was a case-only study [27], one investigated fibrosis but not HCC [10], and two were based on the same participants [19, 28]. Eventually, 12 studies were included in the current meta-analysis (Table 1). No relevant case-control studies were identified based on the alternative polymorphism IDs for rs1012068 (rs56511012, rs58339834, rs386510025) or for rs5998152 (rs61578881, rs8143107).Figure 1
Flowchart of study selection.Table 1
Characteristics of the included studies and genotype distributions.
Study (year of publication)CountryEthnicityn (cases), n (controls)Cohort characteristicsGenotypeAlleleNOS scoreControl sourceGenotyping methodPfor HWEMatched parametersrs1012068TTTGGGTGMiki et al. [12]JapanAsian922HCV-related HCC6082892515053398Human610-quadAge, sex, BMI2390Chronic HCV infection1886470344242538HB0.446Lange et al. [13]SwitzerlandCaucasian64HCV-related HCC3626298307Allele-specific PCRSex1849With chronic hepatitis C9877271352701997HB0.943Liu [14]ChinaAsian320HBV-related HCC157134294481928PCR-RFLPAge, sex320With chronic hepatitis B16413323461179HB0.573Al-Anazi et al. [15]Saudi ArabiaAsian151HCV-related HCC65779207957INNO-LiPA HCV IIBMI574With chronic hepatitis C29724433838310HB0.061Ma et al. [16]ChinaAsian308HBV-related HCC145130334201966MALDI-TOF MS-484With chronic hepatitis B28616929741227HB0.546Hai et al. [17]JapanAsian142HCV-related HCC97405234506TaqMan-575With chronic hepatitis C41215112975175HB0.671Zhang [18]ChinaAsian46HCV-related HCC2418466268MALDI-TOF MSAge, BMI141With chronic hepatitis C8251821567HB0.985Liu et al. [19]ChinaAsian308HBV-related HCC145130334201966MALDI-TOF MS-217With chronic hepatitis B1247914327107HB0.767El-Daly et al. [20]Saudi ArabiaAsian100HCV-related HCC234928951058TaqManAge, sex100Healthy control7124516634HB0.135Sharkawy et al. [21]AustraliaCaucasian188With chronic hepatitis C10265212691078TaqManAge, sex, BMI1501HCV-related HCC7915801302162840HB0.110Hanan et al. [22]EgyptAfrican60With chronic hepatitis C2730384366TaqMan-20HCV-related HCC6771921HB0.182rs5998152TTTCCCTCMiki et al. [12]JapanAsian212HCV-related HCC138686344808Human610-quadAge, sex, BMI765With chronic hepatitis C62413561383147HB0.658Al-Anazi et al. [15]Saudi ArabiaAsian151HCV-related HCC64789206967INNO-LiPA HCV IIBMI574With chronic hepatitis C29823937835313HB0.233Qiao et al. [23]ChinaAsian48HCV-related HCC2419567298MALDI-TOF MSAge, sex, BMI109With chronic hepatitis C6535916553HB0.183Abbreviations: HB, hospital-based; HCV, hepatitis C virus; HBV, hepatitis B virus; HWE, Hardy-Weinberg equilibrium; NOS, Newcastle–Ottawa Scale; BMI, body mass index; -, not reported.A total of 11 studies [12–22] investigated rs1012068, and 3 studies [12, 15, 23] investigated rs5998152. The distribution of genotypes in controls was consistent with Hardy-Weinberg equilibrium (HWE). The average NOS score of the 12 case-control studies was 7.09 points (ranging from 6 to 8 points), which suggested that the methodological quality of the 12 studies was generally adequate.


### 3.2. Quantitative Data Synthesis

#### 3.2.1. rs1012068 and HCC Risk

As shown in Table2 and Figure S1, a meta-analysis based on a population of 2,609 cases and 8,171 in 11 studies [12–22] revealed that the rs1012068 polymorphism did not significantly increase HCC risk in total under the allelic model (OR = 1.32, 95% CI = 1.04–1.67, P = 0.02); the recessive model (OR = 1.42, 95% CI = 0.96–2.10, P = 0.08); the dominant model (OR = 1.43, 95% CI = 1.09–1.87, P = 0.01); the homozygous model (OR = 1.61, 95% CI = 1.01–2.57, P = 0.05); or the heterozygous model (OR = 1.39, 95% CI = 1.09–1.79, P = 0.009).Table 2
Overall meta-analysis of the association of the DEPDC5 rs1012068 and rs5998152 with hepatocellular carcinoma risk.
Genetic modelsNumber of studies (references)OR (95% CI)Z (P value)df (P value)I2 (%)Meta-analysis modelrs1012068Allelic model (G vs. T)Overall11 [9–19]1.32 (1.04, 1.67)2.26 (0.02)10 (<0.001)86RandomAsians8 [10–17]1.56 (1.22, 1.99)3.58 (<0.001)7 (<0.001)84RandomHBV-related3 [11, 13, 16]1.34 (1.16, 1.54)4.05 (<0.001)2 (0.14)49FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.29 (0.91, 1.84)1.43 (0.15)7 (<0.001)90RandomRecessive model (GG vs. TG + TT)Overall11 [9–19]1.42 (0.96, 2.10)1.73 (0.08)10 (0.001)66RandomAsians8 [10–17]1.82 (1.43, 2.30)4.94 (<0.001)7 (0.13)37FixedHBV-related3 [11, 13, 16]1.62 (1.16, 2.26)2.86 (0.004)2 (0.61)0FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.26 (0.68, 2.32)0.73 (0.47)7 (<0.001)75RandomDominant model (GG + TG vs.TT)Overall11 [9–19]1.43 (1.09, 1.87)2.58 (0.01)10 (<0.001)83RandomAsian8 [10–17]1.67 (1.26, 2.22)3.53 (0.004)7 (<0.001)82RandomHBV-related3 [11, 13, 16]1.39(1.16, 1.66)3.57 (<0.001)2 (0.16)45FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.44 (0.97, 2.14)1.82 (0.07)7 (<0.001)87RandomHomozygous model (GG vs. TT)Overall11 [9–19]1.61 (1.01, 2.57)1.98 (0.05)10 (<0.001)75RandomAsians8 [10–17]2.21 (1.42, 3.43)3.51 (<0.001)7 (0.006)64RandomHBV-related3 [11, 13, 16]1.82 (1.29, 2.56)3.44 (<0.001)2 (0.40)0FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.44 (0.70, 2.99)0.99 (0.32)7 (<0.001)81RandomHeterozygous model (TG vs. TT)Overall11 [9–19]1.39 (1.09, 1.79)2.62 (0.009)10 (<0.001)78RandomAsians8 [10–17]1.57 (1.20, 2.04)3.32 (<0.001)7 (<0.001)77RandomHBV-related3 [11, 13, 16]1.31 (1.08, 1.59)2.80 (0.005)2 (0.25)28FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.44 (1.01, 2.07)1.99 (0.05)7 (<0.001)83Randomrs5998152Allelic model (C vs. T)Asians/HCV-related3 [10, 12, 20]1.56 (1.05, 2.33)2.18 (0.03)2 (0.02)75RandomRecessive model (CC vs. TC + TT)Asians/HCV-related3 [10, 12, 20]1.32 (0.77, 2.26)1.02 (0.31)2 (0.14)50FixedDominant model (CC + TC vs.TT)Asians/HCV-related3 [10, 12, 20]1.82 (1.44, 2.30)5.05 (<0.001)2 (0.13)51FixedHomozygous model (CC vs. TT)Asians/HCV-related3 [10, 12, 20]1.62 (0.93, 2.82)1.72 (0.09)2 (0.14)49FixedHeterozygous model (TC vs. TT)Asians/HCV-related3 [10, 12, 20]1.82 (1.43, 2.31)4.89 (<0.001)2 (0.24)30FixedAbbreviations: OR, odds ratio; 95% CI, 95% confidence interval; df, degree of freedom; HBV, hepatitis B virus; HCV, hepatitis C virus.A meta-analysis based on ethnicity for the subgroup of 2,297 Asian cases and 4,801 Asian controls in 8 studies [12, 14–20] showed that the rs1012068 polymorphism significantly increased HCC risk in Asians (Table 2; Figure 2) under the allelic model (OR = 1.56, 95% CI = 1.22–1.99, P < 0.001); the recessive model (OR = 1.82, 95% CI = 1.43–2.30, P < 0.001); the dominant model (OR = 1.67, 95% CI = 1.26–2.22, P = 0.004); the homozygous model (OR = 2.21, 95% CI = 1.42–3.43, P < 0.001); and the heterozygous model (OR = 1.57, 95% CI = 1.20–2.04, P < 0.001). Subgroup analysis in Caucasian populations was not performed because only two studies reported such data.Figure 2
Forest plot showing the relationship between DEPDC5 rs1012068 polymorphism and HCC risk in Asians under different genetic models: (a) allelic (G vs. T), (b) recessive (GG vs. TG + TT), (c) dominant (GG + TG vs. TT), (d) homozygous (GG vs. TT), and (e) heterozygous (TG vs. TT). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HCC, hepatocellular carcinoma; CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel.
(a)(b)(c)(d)(e)Then, we conducted a meta-analysis based on the etiology of HCC, in which both cases and controls were chronically infected with HBV. Results for the subgroup of 936 cases and 1,021 controls in 3 studies [14, 16, 19] showed that the rs1012068 polymorphism significantly increased HCC risk in individuals with chronic HBV infection (Table 2; Figure 3) under the allelic model (OR = 1.34, 95% CI = 1.16–1.54, P < 0.001); the recessive model (OR = 1.62, 95% CI = 1.16–2.26, P = 0.004); the dominant model (OR = 1.39, 95% CI = 1.16–1.66, P < 0.001); the homozygous model (OR = 1.82, 95% CI = 1.29–2.56, P < 0.001); and the heterozygous model (OR = 1.31, 95% CI = 1.08–1.59, P = 0.005).Figure 3
Forest plot showing the relationship between DEPDC5 rs1012068 polymorphism and HCC risk in individuals with chronic HBV infection under different genetic models: (a) allelic (G vs. T), (b) recessive (GG vs. TG + TT), (c) dominant (GG + TG vs. TT), (d) homozygous (GG vs. TT), and (e) heterozygous (TG vs. TT). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel.
(a)(b)(c)(d)(e)Next, a meta-analysis was conducted based on the etiology of HCC, in which both cases and controls were chronically infected with HCV. Results for the subgroup of 1,673 cases and 7,150 controls in 8 studies [12, 13, 15, 17, 18, 20–22] showed that the rs1012068 polymorphism did not significantly increase HCC risk in individuals with chronic HCV infection (Table 2; Figure S2) under the allelic model (OR = 1.46, 95% CI = 1.03–2.05, P = 0.03); the recessive model (OR = 1.63, 95% CI = 1.00–2.66, P = 0.05); the dominant model (OR = 1.56, 95% CI = 1.04–2.34, P = 0.03); the homozygous model (OR = 1.91, 95% CI = 0.99–3.65, P = 0.05); and the heterozygous model (OR = 1.48, 95% CI = 1.02–2.16, P = 0.04).


#### 3.2.2. rs5998152 and HCC Risk

As shown in Table2 and Figure 4, a meta-analysis based on a population of 411 cases and 1,448 controls in 3 studies [12, 15, 23] revealed that the rs5998152 polymorphism was significantly associated with HCC risk in Asians with chronic HCV infection under the allelic model (OR = 1.56, 95% CI = 1.05–2.33, P = 0.03); the dominant model (OR = 1.82, 95% CI = 1.44–2.30, P < 0.001); and the heterozygous model (OR = 1.82, 95% CI = 1.43–2.31, P < 0.001); but not under the recessive model (OR = 1.32, 95% CI = 0.77–2.26, P = 0.31); or the homozygous dominant model (OR = 1.62, 95% CI = 0.93–2.82, P = 0.09).Figure 4
Forest plot showing the relationship between the DEPDC5 rs5998152 polymorphism and HCC risk in Asians with chronic HBV infection under different genetic models: (a) allelic (T vs. C), (b) recessive (TT vs. CT + CC), (c) dominant (CT + TT vs. CC), (d) homozygous (TT vs. CC), and (e) heterozygous (CT vs. CC). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel.
(a)(b)(c)(d)(e)


### 3.3. Sensitivity Analysis

The controls in all 8 case-control studies that investigated the association between the rs1012068 polymorphism and HCC risk were chronically infected with HCV, except the controls in one study [20], in which the controls were healthy individuals. To eliminate such heterogeneity among controls, we repeated the meta-analysis after deleting this study. Repeating the meta-analysis led to similar results as when the study was included, suggesting that our meta-analysis is reliable (Figure S3).


### 3.4. Publication Bias

As shown in Figures5 and 6, Begg’s funnel plot and Egger’s regression test showed that the meta-analysis of rs1012068 and rs5998152 polymorphisms showed no obvious asymmetry under the five genetic models (all P > 0.05).Figure 5
Begg’s funnel plot to assess publication bias in the meta-analysis of the association between the DEPDC5 rs1012068 polymorphism and HCC risk in the total population under different genetic models: (a) allelic (G vs. T), (c) recessive (GG vs. TG + TT), (e) dominant (GG + TG vs. TT), (g) homozygous (GG vs. TT), and (i) heterozygous (TG vs. TT). Egger’s regression test to assess publication bias in the meta-analysis of the association between DEPDC5 rs1012068 polymorphism and HCC risk in the total population under different genetic models: (b) allelic (G vs. T), (d) recessive (GG vs. TG + TT), (f) dominant (GG + TG vs. TT), (h) homozygous (GG vs. TT), and (j) heterozygous (TG vs. TT). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HCC, hepatocellular carcinoma; OR, odds ratio.
(a)(b)(c)(d)(e)(f)(g)(h)(i)(j)Figure 6
Begg’s funnel plot to assess publication bias in the meta-analysis of the association between DEPDC5 rs5998152 polymorphism and HCC risk in the total population under different genetic models: (a) allelic (C vs. T), (c) recessive (CC vs. TC + TT), (e) dominant (CC + TC vs. TT), (g) homozygous (CC vs. TT), and (i) heterozygous (TC vs. TT). Egger’s regression test to assess publication bias in the meta-analysis of the association between DEPDC5 rs5998152 polymorphism and HCC risk in the total population under different genetic models: (b) allelic (C vs. T), (d) recessive (CC vs. TC + TT), (f) dominant (CC + TC vs. TT), (h) homozygous (CC vs. TT), and (j) heterozygous (TC vs. TT). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HCC, hepatocellular carcinoma; OR, odds ratio.
(a)(b)(c)(d)(e)(f)(g)(h)(i)(j)


## 3.1. Characteristics of Primary Studies

The flowchart of study selection is summarized in Figure1, and search strategies for each database are presented in Table S1. After a comprehensive search of the databases using the search strategies in Table S1, 54 relevant studies were compliant with the search strategy, of which 28 were excluded due to being duplicates. Another 11 were omitted after screening titles and abstracts. Among the 15 studies remaining, one was a case-only study [27], one investigated fibrosis but not HCC [10], and two were based on the same participants [19, 28]. Eventually, 12 studies were included in the current meta-analysis (Table 1). No relevant case-control studies were identified based on the alternative polymorphism IDs for rs1012068 (rs56511012, rs58339834, rs386510025) or for rs5998152 (rs61578881, rs8143107).Figure 1
Flowchart of study selection.Table 1
Characteristics of the included studies and genotype distributions.
Study (year of publication)CountryEthnicityn (cases), n (controls)Cohort characteristicsGenotypeAlleleNOS scoreControl sourceGenotyping methodPfor HWEMatched parametersrs1012068TTTGGGTGMiki et al. [12]JapanAsian922HCV-related HCC6082892515053398Human610-quadAge, sex, BMI2390Chronic HCV infection1886470344242538HB0.446Lange et al. [13]SwitzerlandCaucasian64HCV-related HCC3626298307Allele-specific PCRSex1849With chronic hepatitis C9877271352701997HB0.943Liu [14]ChinaAsian320HBV-related HCC157134294481928PCR-RFLPAge, sex320With chronic hepatitis B16413323461179HB0.573Al-Anazi et al. [15]Saudi ArabiaAsian151HCV-related HCC65779207957INNO-LiPA HCV IIBMI574With chronic hepatitis C29724433838310HB0.061Ma et al. [16]ChinaAsian308HBV-related HCC145130334201966MALDI-TOF MS-484With chronic hepatitis B28616929741227HB0.546Hai et al. [17]JapanAsian142HCV-related HCC97405234506TaqMan-575With chronic hepatitis C41215112975175HB0.671Zhang [18]ChinaAsian46HCV-related HCC2418466268MALDI-TOF MSAge, BMI141With chronic hepatitis C8251821567HB0.985Liu et al. [19]ChinaAsian308HBV-related HCC145130334201966MALDI-TOF MS-217With chronic hepatitis B1247914327107HB0.767El-Daly et al. [20]Saudi ArabiaAsian100HCV-related HCC234928951058TaqManAge, sex100Healthy control7124516634HB0.135Sharkawy et al. [21]AustraliaCaucasian188With chronic hepatitis C10265212691078TaqManAge, sex, BMI1501HCV-related HCC7915801302162840HB0.110Hanan et al. [22]EgyptAfrican60With chronic hepatitis C2730384366TaqMan-20HCV-related HCC6771921HB0.182rs5998152TTTCCCTCMiki et al. [12]JapanAsian212HCV-related HCC138686344808Human610-quadAge, sex, BMI765With chronic hepatitis C62413561383147HB0.658Al-Anazi et al. [15]Saudi ArabiaAsian151HCV-related HCC64789206967INNO-LiPA HCV IIBMI574With chronic hepatitis C29823937835313HB0.233Qiao et al. [23]ChinaAsian48HCV-related HCC2419567298MALDI-TOF MSAge, sex, BMI109With chronic hepatitis C6535916553HB0.183Abbreviations: HB, hospital-based; HCV, hepatitis C virus; HBV, hepatitis B virus; HWE, Hardy-Weinberg equilibrium; NOS, Newcastle–Ottawa Scale; BMI, body mass index; -, not reported.A total of 11 studies [12–22] investigated rs1012068, and 3 studies [12, 15, 23] investigated rs5998152. The distribution of genotypes in controls was consistent with Hardy-Weinberg equilibrium (HWE). The average NOS score of the 12 case-control studies was 7.09 points (ranging from 6 to 8 points), which suggested that the methodological quality of the 12 studies was generally adequate.


## 3.2. Quantitative Data Synthesis

### 3.2.1. rs1012068 and HCC Risk

As shown in Table2 and Figure S1, a meta-analysis based on a population of 2,609 cases and 8,171 in 11 studies [12–22] revealed that the rs1012068 polymorphism did not significantly increase HCC risk in total under the allelic model (OR = 1.32, 95% CI = 1.04–1.67, P = 0.02); the recessive model (OR = 1.42, 95% CI = 0.96–2.10, P = 0.08); the dominant model (OR = 1.43, 95% CI = 1.09–1.87, P = 0.01); the homozygous model (OR = 1.61, 95% CI = 1.01–2.57, P = 0.05); or the heterozygous model (OR = 1.39, 95% CI = 1.09–1.79, P = 0.009).Table 2
Overall meta-analysis of the association of the DEPDC5 rs1012068 and rs5998152 with hepatocellular carcinoma risk.
Genetic modelsNumber of studies (references)OR (95% CI)Z (P value)df (P value)I2 (%)Meta-analysis modelrs1012068Allelic model (G vs. T)Overall11 [9–19]1.32 (1.04, 1.67)2.26 (0.02)10 (<0.001)86RandomAsians8 [10–17]1.56 (1.22, 1.99)3.58 (<0.001)7 (<0.001)84RandomHBV-related3 [11, 13, 16]1.34 (1.16, 1.54)4.05 (<0.001)2 (0.14)49FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.29 (0.91, 1.84)1.43 (0.15)7 (<0.001)90RandomRecessive model (GG vs. TG + TT)Overall11 [9–19]1.42 (0.96, 2.10)1.73 (0.08)10 (0.001)66RandomAsians8 [10–17]1.82 (1.43, 2.30)4.94 (<0.001)7 (0.13)37FixedHBV-related3 [11, 13, 16]1.62 (1.16, 2.26)2.86 (0.004)2 (0.61)0FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.26 (0.68, 2.32)0.73 (0.47)7 (<0.001)75RandomDominant model (GG + TG vs.TT)Overall11 [9–19]1.43 (1.09, 1.87)2.58 (0.01)10 (<0.001)83RandomAsian8 [10–17]1.67 (1.26, 2.22)3.53 (0.004)7 (<0.001)82RandomHBV-related3 [11, 13, 16]1.39(1.16, 1.66)3.57 (<0.001)2 (0.16)45FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.44 (0.97, 2.14)1.82 (0.07)7 (<0.001)87RandomHomozygous model (GG vs. TT)Overall11 [9–19]1.61 (1.01, 2.57)1.98 (0.05)10 (<0.001)75RandomAsians8 [10–17]2.21 (1.42, 3.43)3.51 (<0.001)7 (0.006)64RandomHBV-related3 [11, 13, 16]1.82 (1.29, 2.56)3.44 (<0.001)2 (0.40)0FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.44 (0.70, 2.99)0.99 (0.32)7 (<0.001)81RandomHeterozygous model (TG vs. TT)Overall11 [9–19]1.39 (1.09, 1.79)2.62 (0.009)10 (<0.001)78RandomAsians8 [10–17]1.57 (1.20, 2.04)3.32 (<0.001)7 (<0.001)77RandomHBV-related3 [11, 13, 16]1.31 (1.08, 1.59)2.80 (0.005)2 (0.25)28FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.44 (1.01, 2.07)1.99 (0.05)7 (<0.001)83Randomrs5998152Allelic model (C vs. T)Asians/HCV-related3 [10, 12, 20]1.56 (1.05, 2.33)2.18 (0.03)2 (0.02)75RandomRecessive model (CC vs. TC + TT)Asians/HCV-related3 [10, 12, 20]1.32 (0.77, 2.26)1.02 (0.31)2 (0.14)50FixedDominant model (CC + TC vs.TT)Asians/HCV-related3 [10, 12, 20]1.82 (1.44, 2.30)5.05 (<0.001)2 (0.13)51FixedHomozygous model (CC vs. TT)Asians/HCV-related3 [10, 12, 20]1.62 (0.93, 2.82)1.72 (0.09)2 (0.14)49FixedHeterozygous model (TC vs. TT)Asians/HCV-related3 [10, 12, 20]1.82 (1.43, 2.31)4.89 (<0.001)2 (0.24)30FixedAbbreviations: OR, odds ratio; 95% CI, 95% confidence interval; df, degree of freedom; HBV, hepatitis B virus; HCV, hepatitis C virus.A meta-analysis based on ethnicity for the subgroup of 2,297 Asian cases and 4,801 Asian controls in 8 studies [12, 14–20] showed that the rs1012068 polymorphism significantly increased HCC risk in Asians (Table 2; Figure 2) under the allelic model (OR = 1.56, 95% CI = 1.22–1.99, P < 0.001); the recessive model (OR = 1.82, 95% CI = 1.43–2.30, P < 0.001); the dominant model (OR = 1.67, 95% CI = 1.26–2.22, P = 0.004); the homozygous model (OR = 2.21, 95% CI = 1.42–3.43, P < 0.001); and the heterozygous model (OR = 1.57, 95% CI = 1.20–2.04, P < 0.001). Subgroup analysis in Caucasian populations was not performed because only two studies reported such data.Figure 2
Forest plot showing the relationship between DEPDC5 rs1012068 polymorphism and HCC risk in Asians under different genetic models: (a) allelic (G vs. T), (b) recessive (GG vs. TG + TT), (c) dominant (GG + TG vs. TT), (d) homozygous (GG vs. TT), and (e) heterozygous (TG vs. TT). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HCC, hepatocellular carcinoma; CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel.
(a)(b)(c)(d)(e)Then, we conducted a meta-analysis based on the etiology of HCC, in which both cases and controls were chronically infected with HBV. Results for the subgroup of 936 cases and 1,021 controls in 3 studies [14, 16, 19] showed that the rs1012068 polymorphism significantly increased HCC risk in individuals with chronic HBV infection (Table 2; Figure 3) under the allelic model (OR = 1.34, 95% CI = 1.16–1.54, P < 0.001); the recessive model (OR = 1.62, 95% CI = 1.16–2.26, P = 0.004); the dominant model (OR = 1.39, 95% CI = 1.16–1.66, P < 0.001); the homozygous model (OR = 1.82, 95% CI = 1.29–2.56, P < 0.001); and the heterozygous model (OR = 1.31, 95% CI = 1.08–1.59, P = 0.005).Figure 3
Forest plot showing the relationship between DEPDC5 rs1012068 polymorphism and HCC risk in individuals with chronic HBV infection under different genetic models: (a) allelic (G vs. T), (b) recessive (GG vs. TG + TT), (c) dominant (GG + TG vs. TT), (d) homozygous (GG vs. TT), and (e) heterozygous (TG vs. TT). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel.
(a)(b)(c)(d)(e)Next, a meta-analysis was conducted based on the etiology of HCC, in which both cases and controls were chronically infected with HCV. Results for the subgroup of 1,673 cases and 7,150 controls in 8 studies [12, 13, 15, 17, 18, 20–22] showed that the rs1012068 polymorphism did not significantly increase HCC risk in individuals with chronic HCV infection (Table 2; Figure S2) under the allelic model (OR = 1.46, 95% CI = 1.03–2.05, P = 0.03); the recessive model (OR = 1.63, 95% CI = 1.00–2.66, P = 0.05); the dominant model (OR = 1.56, 95% CI = 1.04–2.34, P = 0.03); the homozygous model (OR = 1.91, 95% CI = 0.99–3.65, P = 0.05); and the heterozygous model (OR = 1.48, 95% CI = 1.02–2.16, P = 0.04).


### 3.2.2. rs5998152 and HCC Risk

As shown in Table2 and Figure 4, a meta-analysis based on a population of 411 cases and 1,448 controls in 3 studies [12, 15, 23] revealed that the rs5998152 polymorphism was significantly associated with HCC risk in Asians with chronic HCV infection under the allelic model (OR = 1.56, 95% CI = 1.05–2.33, P = 0.03); the dominant model (OR = 1.82, 95% CI = 1.44–2.30, P < 0.001); and the heterozygous model (OR = 1.82, 95% CI = 1.43–2.31, P < 0.001); but not under the recessive model (OR = 1.32, 95% CI = 0.77–2.26, P = 0.31); or the homozygous dominant model (OR = 1.62, 95% CI = 0.93–2.82, P = 0.09).Figure 4
Forest plot showing the relationship between the DEPDC5 rs5998152 polymorphism and HCC risk in Asians with chronic HBV infection under different genetic models: (a) allelic (T vs. C), (b) recessive (TT vs. CT + CC), (c) dominant (CT + TT vs. CC), (d) homozygous (TT vs. CC), and (e) heterozygous (CT vs. CC). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel.
(a)(b)(c)(d)(e)


## 3.2.1. rs1012068 and HCC Risk

As shown in Table2 and Figure S1, a meta-analysis based on a population of 2,609 cases and 8,171 in 11 studies [12–22] revealed that the rs1012068 polymorphism did not significantly increase HCC risk in total under the allelic model (OR = 1.32, 95% CI = 1.04–1.67, P = 0.02); the recessive model (OR = 1.42, 95% CI = 0.96–2.10, P = 0.08); the dominant model (OR = 1.43, 95% CI = 1.09–1.87, P = 0.01); the homozygous model (OR = 1.61, 95% CI = 1.01–2.57, P = 0.05); or the heterozygous model (OR = 1.39, 95% CI = 1.09–1.79, P = 0.009).Table 2
Overall meta-analysis of the association of the DEPDC5 rs1012068 and rs5998152 with hepatocellular carcinoma risk.
Genetic modelsNumber of studies (references)OR (95% CI)Z (P value)df (P value)I2 (%)Meta-analysis modelrs1012068Allelic model (G vs. T)Overall11 [9–19]1.32 (1.04, 1.67)2.26 (0.02)10 (<0.001)86RandomAsians8 [10–17]1.56 (1.22, 1.99)3.58 (<0.001)7 (<0.001)84RandomHBV-related3 [11, 13, 16]1.34 (1.16, 1.54)4.05 (<0.001)2 (0.14)49FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.29 (0.91, 1.84)1.43 (0.15)7 (<0.001)90RandomRecessive model (GG vs. TG + TT)Overall11 [9–19]1.42 (0.96, 2.10)1.73 (0.08)10 (0.001)66RandomAsians8 [10–17]1.82 (1.43, 2.30)4.94 (<0.001)7 (0.13)37FixedHBV-related3 [11, 13, 16]1.62 (1.16, 2.26)2.86 (0.004)2 (0.61)0FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.26 (0.68, 2.32)0.73 (0.47)7 (<0.001)75RandomDominant model (GG + TG vs.TT)Overall11 [9–19]1.43 (1.09, 1.87)2.58 (0.01)10 (<0.001)83RandomAsian8 [10–17]1.67 (1.26, 2.22)3.53 (0.004)7 (<0.001)82RandomHBV-related3 [11, 13, 16]1.39(1.16, 1.66)3.57 (<0.001)2 (0.16)45FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.44 (0.97, 2.14)1.82 (0.07)7 (<0.001)87RandomHomozygous model (GG vs. TT)Overall11 [9–19]1.61 (1.01, 2.57)1.98 (0.05)10 (<0.001)75RandomAsians8 [10–17]2.21 (1.42, 3.43)3.51 (<0.001)7 (0.006)64RandomHBV-related3 [11, 13, 16]1.82 (1.29, 2.56)3.44 (<0.001)2 (0.40)0FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.44 (0.70, 2.99)0.99 (0.32)7 (<0.001)81RandomHeterozygous model (TG vs. TT)Overall11 [9–19]1.39 (1.09, 1.79)2.62 (0.009)10 (<0.001)78RandomAsians8 [10–17]1.57 (1.20, 2.04)3.32 (<0.001)7 (<0.001)77RandomHBV-related3 [11, 13, 16]1.31 (1.08, 1.59)2.80 (0.005)2 (0.25)28FixedHCV-related8 [9, 10, 12, 14, 15, 17–19]1.44 (1.01, 2.07)1.99 (0.05)7 (<0.001)83Randomrs5998152Allelic model (C vs. T)Asians/HCV-related3 [10, 12, 20]1.56 (1.05, 2.33)2.18 (0.03)2 (0.02)75RandomRecessive model (CC vs. TC + TT)Asians/HCV-related3 [10, 12, 20]1.32 (0.77, 2.26)1.02 (0.31)2 (0.14)50FixedDominant model (CC + TC vs.TT)Asians/HCV-related3 [10, 12, 20]1.82 (1.44, 2.30)5.05 (<0.001)2 (0.13)51FixedHomozygous model (CC vs. TT)Asians/HCV-related3 [10, 12, 20]1.62 (0.93, 2.82)1.72 (0.09)2 (0.14)49FixedHeterozygous model (TC vs. TT)Asians/HCV-related3 [10, 12, 20]1.82 (1.43, 2.31)4.89 (<0.001)2 (0.24)30FixedAbbreviations: OR, odds ratio; 95% CI, 95% confidence interval; df, degree of freedom; HBV, hepatitis B virus; HCV, hepatitis C virus.A meta-analysis based on ethnicity for the subgroup of 2,297 Asian cases and 4,801 Asian controls in 8 studies [12, 14–20] showed that the rs1012068 polymorphism significantly increased HCC risk in Asians (Table 2; Figure 2) under the allelic model (OR = 1.56, 95% CI = 1.22–1.99, P < 0.001); the recessive model (OR = 1.82, 95% CI = 1.43–2.30, P < 0.001); the dominant model (OR = 1.67, 95% CI = 1.26–2.22, P = 0.004); the homozygous model (OR = 2.21, 95% CI = 1.42–3.43, P < 0.001); and the heterozygous model (OR = 1.57, 95% CI = 1.20–2.04, P < 0.001). Subgroup analysis in Caucasian populations was not performed because only two studies reported such data.Figure 2
Forest plot showing the relationship between DEPDC5 rs1012068 polymorphism and HCC risk in Asians under different genetic models: (a) allelic (G vs. T), (b) recessive (GG vs. TG + TT), (c) dominant (GG + TG vs. TT), (d) homozygous (GG vs. TT), and (e) heterozygous (TG vs. TT). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HCC, hepatocellular carcinoma; CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel.
(a)(b)(c)(d)(e)Then, we conducted a meta-analysis based on the etiology of HCC, in which both cases and controls were chronically infected with HBV. Results for the subgroup of 936 cases and 1,021 controls in 3 studies [14, 16, 19] showed that the rs1012068 polymorphism significantly increased HCC risk in individuals with chronic HBV infection (Table 2; Figure 3) under the allelic model (OR = 1.34, 95% CI = 1.16–1.54, P < 0.001); the recessive model (OR = 1.62, 95% CI = 1.16–2.26, P = 0.004); the dominant model (OR = 1.39, 95% CI = 1.16–1.66, P < 0.001); the homozygous model (OR = 1.82, 95% CI = 1.29–2.56, P < 0.001); and the heterozygous model (OR = 1.31, 95% CI = 1.08–1.59, P = 0.005).Figure 3
Forest plot showing the relationship between DEPDC5 rs1012068 polymorphism and HCC risk in individuals with chronic HBV infection under different genetic models: (a) allelic (G vs. T), (b) recessive (GG vs. TG + TT), (c) dominant (GG + TG vs. TT), (d) homozygous (GG vs. TT), and (e) heterozygous (TG vs. TT). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel.
(a)(b)(c)(d)(e)Next, a meta-analysis was conducted based on the etiology of HCC, in which both cases and controls were chronically infected with HCV. Results for the subgroup of 1,673 cases and 7,150 controls in 8 studies [12, 13, 15, 17, 18, 20–22] showed that the rs1012068 polymorphism did not significantly increase HCC risk in individuals with chronic HCV infection (Table 2; Figure S2) under the allelic model (OR = 1.46, 95% CI = 1.03–2.05, P = 0.03); the recessive model (OR = 1.63, 95% CI = 1.00–2.66, P = 0.05); the dominant model (OR = 1.56, 95% CI = 1.04–2.34, P = 0.03); the homozygous model (OR = 1.91, 95% CI = 0.99–3.65, P = 0.05); and the heterozygous model (OR = 1.48, 95% CI = 1.02–2.16, P = 0.04).


## 3.2.2. rs5998152 and HCC Risk

As shown in Table2 and Figure 4, a meta-analysis based on a population of 411 cases and 1,448 controls in 3 studies [12, 15, 23] revealed that the rs5998152 polymorphism was significantly associated with HCC risk in Asians with chronic HCV infection under the allelic model (OR = 1.56, 95% CI = 1.05–2.33, P = 0.03); the dominant model (OR = 1.82, 95% CI = 1.44–2.30, P < 0.001); and the heterozygous model (OR = 1.82, 95% CI = 1.43–2.31, P < 0.001); but not under the recessive model (OR = 1.32, 95% CI = 0.77–2.26, P = 0.31); or the homozygous dominant model (OR = 1.62, 95% CI = 0.93–2.82, P = 0.09).Figure 4
Forest plot showing the relationship between the DEPDC5 rs5998152 polymorphism and HCC risk in Asians with chronic HBV infection under different genetic models: (a) allelic (T vs. C), (b) recessive (TT vs. CT + CC), (c) dominant (CT + TT vs. CC), (d) homozygous (TT vs. CC), and (e) heterozygous (CT vs. CC). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel.
(a)(b)(c)(d)(e)


## 3.3. Sensitivity Analysis

The controls in all 8 case-control studies that investigated the association between the rs1012068 polymorphism and HCC risk were chronically infected with HCV, except the controls in one study [20], in which the controls were healthy individuals. To eliminate such heterogeneity among controls, we repeated the meta-analysis after deleting this study. Repeating the meta-analysis led to similar results as when the study was included, suggesting that our meta-analysis is reliable (Figure S3).


## 3.4. Publication Bias

As shown in Figures5 and 6, Begg’s funnel plot and Egger’s regression test showed that the meta-analysis of rs1012068 and rs5998152 polymorphisms showed no obvious asymmetry under the five genetic models (all P > 0.05).Figure 5
Begg’s funnel plot to assess publication bias in the meta-analysis of the association between the DEPDC5 rs1012068 polymorphism and HCC risk in the total population under different genetic models: (a) allelic (G vs. T), (c) recessive (GG vs. TG + TT), (e) dominant (GG + TG vs. TT), (g) homozygous (GG vs. TT), and (i) heterozygous (TG vs. TT). Egger’s regression test to assess publication bias in the meta-analysis of the association between DEPDC5 rs1012068 polymorphism and HCC risk in the total population under different genetic models: (b) allelic (G vs. T), (d) recessive (GG vs. TG + TT), (f) dominant (GG + TG vs. TT), (h) homozygous (GG vs. TT), and (j) heterozygous (TG vs. TT). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HCC, hepatocellular carcinoma; OR, odds ratio.
(a)(b)(c)(d)(e)(f)(g)(h)(i)(j)Figure 6
Begg’s funnel plot to assess publication bias in the meta-analysis of the association between DEPDC5 rs5998152 polymorphism and HCC risk in the total population under different genetic models: (a) allelic (C vs. T), (c) recessive (CC vs. TC + TT), (e) dominant (CC + TC vs. TT), (g) homozygous (CC vs. TT), and (i) heterozygous (TC vs. TT). Egger’s regression test to assess publication bias in the meta-analysis of the association between DEPDC5 rs5998152 polymorphism and HCC risk in the total population under different genetic models: (b) allelic (C vs. T), (d) recessive (CC vs. TC + TT), (f) dominant (CC + TC vs. TT), (h) homozygous (CC vs. TT), and (j) heterozygous (TC vs. TT). Abbreviations: DEPDC5, pleckstrin domain-containing protein 5; HCC, hepatocellular carcinoma; OR, odds ratio.
(a)(b)(c)(d)(e)(f)(g)(h)(i)(j)


## 4. Discussion

In the case of rs1012068, an overall meta-analysis of the total population indicated a significant association with increased HCC risk, regardless of HCC etiology and source of controls. Subgroup analysis based on ethnicity supported this association for Asians. Subsequently, meta-analyses of individuals chronically infected with HBV or HCV were performed. The cases and controls in three case-control studies [14, 16, 19] were all chronically infected with HBV, and in this uniform sample, results showed that the rs1012068 polymorphism significantly increased HCC risk in individuals with chronic HBV infection. In contrast, the association between the rs1012068 polymorphism and HCV-related HCC risk was not significant.In the case of rs5998152, three case-control studies examined a potential relationship between this polymorphism and the risk of HCV-related HCC [12, 15, 23]. All cases and controls were chronically infected with HCV. Results showed the rs5998152 polymorphism was significantly associated with HCC risk in Asians with chronic HCV infection under allelic, dominant, and heterozygous models.It may be that these polymorphisms weaken the activity of DEPDC5, preventing it from inhibiting mTORC1 as it does normally, which in turn leads to pathogenic inflammation and cell growth in the liver [22, 29]. Future research should explore how the rs1012068 and rs5998152 polymorphisms affect DEPDC5 expression and activity.Although positive results were obtained, some limitations that may affect the interpretation of the meta-analysis were presented in this work. First, samples were relatively small due to the lack of case-control studies, especially for rs5998152. Second, among studies investigating the association between the rs1012068 polymorphism and HCC risk, the controls in all case-control studies except one [20] were chronically infected with HCV. When one study with healthy controls was deleted from the meta-analysis [20], the results were not substantially altered, suggesting that our meta-analysis is reliable. Third, the included studies in our meta-analysis spanned 2011–2022, during which antiviral treatments have improved and been widely used for treating HCV- or HBV-related liver disease [30, 31]. Since the included studies did not report detailed data on the use of such therapies, further research should explore how they influence the risk of HCC in individuals with DEPDC5 polymorphisms. Fourth, the robustness of the current meta-analysis may be reduced because the case-control studies involved used different genotyping methods that may differ in sensitivity and specificity, and potentially by other confounding factors such as age, sex, alcohol intake, and tumor status. Given these various limitations, the findings of our meta-analysis should be validated and extended in large, well-designed studies.In summary, our study suggests that the DEPDC5 rs1012068 polymorphism increases HCC risk, especially in Asians with chronic HBV infection, while the rs5998152 polymorphism increases HCC risk in Asians with HCV infection. Further large, well-designed studies are required to validate these findings.



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*Source: 5957481-2023-01-24.xml*