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. 2023 Jan 24;2023:5957481. doi: 10.1155/2023/5957481

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

Shaoliang Zhu 1, Zhenyong Tang 1, Mengjie Zou 2, Tingting Tan 1, Yi Tang 1, Yuanyuan Chen 1, Bin Liang 1, Dongyi Xie 1, Yongyu Yang 1, Shaowei Xie 1, Guangyuan Xie 1, Xiaofeng Dong 1,✉, Tianqi Liu 3,✉, Yuntian Tang 1,✉, Jianrong Yang 1,✉
PMCID: PMC9889158  PMID: 36733671

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.

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

  1. The study cohorts included DEPDC5 rs1012068 and rs5998152 polymorphisms in patients with HCC

  2. Histological features were assessed by liver biopsy, and diagnostic criteria were clearly stated

  3. Unrelated case-control studies were included

  4. If two (or more) studies included the same cohort, only the most recent was included

  5. 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

  1. The source of cases was unclear

  2. No clear diagnostic criteria for HCC were described

  3. The study was a duplicate publication

  4. The study was a review, meta-analysis, comment, or conference abstract

  5. 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, with P < 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 Figure 1, 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.

Figure 1

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Flowchart of study selection.

Table 1.

Characteristics of the included studies and genotype distributions.

Study (year of publication) Country Ethnicity n (cases), n (controls) Cohort characteristics Genotype Allele NOS score Control source Genotyping method Pfor HWE Matched parameters
rs1012068 TT TG GG T G  
Miki et al. [12] Japan Asian 922 HCV-related HCC 608 289 25 1505 339 8   Human610-quad   Age, sex, BMI
  2390 Chronic HCV infection 1886 470 34 4242 538   HB   0.446  
Lange et al. [13] Switzerland Caucasian 64 HCV-related HCC 36 26 2 98 30 7   Allele-specific PCR   Sex
  1849 With chronic hepatitis C 987 727 135 2701 997   HB   0.943  
Liu [14] China Asian 320 HBV-related HCC 157 134 29 448 192 8   PCR-RFLP   Age, sex
  320 With chronic hepatitis B 164 133 23 461 179   HB   0.573  
Al-Anazi et al. [15] Saudi Arabia Asian 151 HCV-related HCC 65 77 9 207 95 7   INNO-LiPA HCV II   BMI
  574 With chronic hepatitis C 297 244 33 838 310   HB   0.061  
Ma et al. [16] China Asian 308 HBV-related HCC 145 130 33 420 196 6   MALDI-TOF MS   -
  484 With chronic hepatitis B 286 169 29 741 227   HB   0.546  
Hai et al. [17] Japan Asian 142 HCV-related HCC 97 40 5 234 50 6   TaqMan   -
  575 With chronic hepatitis C 412 151 12 975 175   HB   0.671  
Zhang [18] China Asian 46 HCV-related HCC 24 18 4 66 26 8   MALDI-TOF MS   Age, BMI
  141 With chronic hepatitis C 82 51 8 215 67   HB   0.985  
Liu et al. [19] China Asian 308 HBV-related HCC 145 130 33 420 196 6   MALDI-TOF MS   -
  217 With chronic hepatitis B 124 79 14 327 107   HB   0.767  
El-Daly et al. [20] Saudi Arabia Asian 100 HCV-related HCC 23 49 28 95 105 8   TaqMan   Age, sex
  100 Healthy control 71 24 5 166 34   HB   0.135  
Sharkawy et al. [21] Australia Caucasian 188 With chronic hepatitis C 102 65 21 269 107 8   TaqMan   Age, sex, BMI
  1501 HCV-related HCC 791 580 130 2162 840   HB   0.110  
Hanan et al. [22] Egypt African 60 With chronic hepatitis C 27 30 3 84 36 6   TaqMan   -
  20 HCV-related HCC 6 7 7 19 21   HB   0.182  
rs5998152 TT TC CC T C  
Miki et al. [12] Japan Asian 212 HCV-related HCC 138 68 6 344 80 8   Human610-quad   Age, sex, BMI
  765 With chronic hepatitis C 624 135 6 1383 147   HB   0.658  
Al-Anazi et al. [15] Saudi Arabia Asian 151 HCV-related HCC 64 78 9 206 96 7   INNO-LiPA HCV II   BMI
  574 With chronic hepatitis C 298 239 37 835 313   HB   0.233  
Qiao et al. [23] China Asian 48 HCV-related HCC 24 19 5 67 29 8   MALDI-TOF MS   Age, sex, BMI
  109 With chronic hepatitis C 65 35 9 165 53   HB   0.183  
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Abbreviations: 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 Table 2 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 models   Number of studies (references) OR (95% CI) Z (P value) df (P value) I 2 (%) Meta-analysis model
rs1012068
Allelic model (G vs. T) Overall 11 [9–19] 1.32 (1.04, 1.67) 2.26 (0.02) 10 (<0.001) 86 Random
Asians 8 [10–17] 1.56 (1.22, 1.99) 3.58 (<0.001) 7 (<0.001) 84 Random
HBV-related 3 [11, 13, 16] 1.34 (1.16, 1.54) 4.05 (<0.001) 2 (0.14) 49 Fixed
HCV-related 8 [9, 10, 12, 14, 15, 17–19] 1.29 (0.91, 1.84) 1.43 (0.15) 7 (<0.001) 90 Random
Recessive model (GG vs. TG + TT) Overall 11 [9–19] 1.42 (0.96, 2.10) 1.73 (0.08) 10 (0.001) 66 Random
Asians 8 [10–17] 1.82 (1.43, 2.30) 4.94 (<0.001) 7 (0.13) 37 Fixed
HBV-related 3 [11, 13, 16] 1.62 (1.16, 2.26) 2.86 (0.004) 2 (0.61) 0 Fixed
HCV-related 8 [9, 10, 12, 14, 15, 17–19] 1.26 (0.68, 2.32) 0.73 (0.47) 7 (<0.001) 75 Random
Dominant model (GG + TG vs.TT) Overall 11 [9–19] 1.43 (1.09, 1.87) 2.58 (0.01) 10 (<0.001) 83 Random
Asian 8 [10–17] 1.67 (1.26, 2.22) 3.53 (0.004) 7 (<0.001) 82 Random
HBV-related 3 [11, 13, 16] 1.39(1.16, 1.66) 3.57 (<0.001) 2 (0.16) 45 Fixed
HCV-related 8 [9, 10, 12, 14, 15, 17–19] 1.44 (0.97, 2.14) 1.82 (0.07) 7 (<0.001) 87 Random
Homozygous model (GG vs. TT) Overall 11 [9–19] 1.61 (1.01, 2.57) 1.98 (0.05) 10 (<0.001) 75 Random
Asians 8 [10–17] 2.21 (1.42, 3.43) 3.51 (<0.001) 7 (0.006) 64 Random
HBV-related 3 [11, 13, 16] 1.82 (1.29, 2.56) 3.44 (<0.001) 2 (0.40) 0 Fixed
HCV-related 8 [9, 10, 12, 14, 15, 17–19] 1.44 (0.70, 2.99) 0.99 (0.32) 7 (<0.001) 81 Random
Heterozygous model (TG vs. TT) Overall 11 [9–19] 1.39 (1.09, 1.79) 2.62 (0.009) 10 (<0.001) 78 Random
Asians 8 [10–17] 1.57 (1.20, 2.04) 3.32 (<0.001) 7 (<0.001) 77 Random
HBV-related 3 [11, 13, 16] 1.31 (1.08, 1.59) 2.80 (0.005) 2 (0.25) 28 Fixed
HCV-related 8 [9, 10, 12, 14, 15, 17–19] 1.44 (1.01, 2.07) 1.99 (0.05) 7 (<0.001) 83 Random
rs5998152
Allelic model (C vs. T) Asians/HCV-related 3 [10, 12, 20] 1.56 (1.05, 2.33) 2.18 (0.03) 2 (0.02) 75 Random
Recessive model (CC vs. TC + TT) Asians/HCV-related 3 [10, 12, 20] 1.32 (0.77, 2.26) 1.02 (0.31) 2 (0.14) 50 Fixed
Dominant model (CC + TC vs.TT) Asians/HCV-related 3 [10, 12, 20] 1.82 (1.44, 2.30) 5.05 (<0.001) 2 (0.13) 51 Fixed
Homozygous model (CC vs. TT) Asians/HCV-related 3 [10, 12, 20] 1.62 (0.93, 2.82) 1.72 (0.09) 2 (0.14) 49 Fixed
Heterozygous model (TC vs. TT) Asians/HCV-related 3 [10, 12, 20] 1.82 (1.43, 2.31) 4.89 (<0.001) 2 (0.24) 30 Fixed
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Abbreviations: 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.

Figure 2

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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.

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.

Figure 3

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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.

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 Table 2 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.

Figure 4

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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.

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 Figures 5 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.

Figure 5

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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.

Figure 6.

Figure 6

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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.

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.

Contributor Information

Xiaofeng Dong, Email: gandanyingcai@163.com.

Tianqi Liu, Email: gxljrqt@163.com.

Yuntian Tang, Email: tangyuntian2021@163.com.

Jianrong Yang, Email: yangjianrong2022@163.com.

Data Availability

The data used to support the findings of this study are included within the article.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

Shaoliang Zhu, Zhenyong Tang, and Mengjie Zou contributed equally to this work.

Supplementary Materials

Supplementary Materials

Figure S1. Forest plot showing the relationship between the DEPDC5 rs1012068 polymorphism and HCC risk in the total population 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). Figure S2. Forest plot showing the relationship between DEPDC5 rs1012068 polymorphism and HCC risk in individuals with chronic HCV 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). Figure S3. Forest plot showing the relationship between the DEPDC5 rs1012068 polymorphism and HCC risk in sensitivity analysis: (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). Table S1. Search strategies for each database.

Click here for additional data file. (3MB, zip)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Materials

Figure S1. Forest plot showing the relationship between the DEPDC5 rs1012068 polymorphism and HCC risk in the total population 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). Figure S2. Forest plot showing the relationship between DEPDC5 rs1012068 polymorphism and HCC risk in individuals with chronic HCV 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). Figure S3. Forest plot showing the relationship between the DEPDC5 rs1012068 polymorphism and HCC risk in sensitivity analysis: (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). Table S1. Search strategies for each database.

Click here for additional data file. (3MB, zip)

Data Availability Statement

The data used to support the findings of this study are included within the article.

Articles from Journal of Oncology are provided here courtesy of Wiley

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