Functional genetic variant of WW domain-containing oxidoreductase (WWOX) gene is associated with hepatocellular carcinoma risk

Lee, Hsiang-Lin; Cheng, Hong; Liu, Yu-Fan; Chou, Ming‐Chih; Yang, Shun‐Fa; Chou, Ying‐Erh

doi:10.1371/journal.pone.0176141

Cited by 19 publications

(29 citation statements)

References 63 publications

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“…After full-text review, six articles were excluded due to no detailed data. Therefore, a total of eight case–control studies were ultimately included in the meta-analysis, 15 – 22 and the details of each study were recorded in Table 1 . Among them, eight articles containing 6,177 cases and 6,606 controls surveyed the association between rs3764340 C>G and malignant tumor risk.…”

Section: Resultsmentioning

confidence: 99%

“… 15 – 22 Four studies on the relation between rs12918952 G>A and malignant tumor risk included 2,447 cases and 3,249 controls, 18 , 20 – 22 and four publications containing 2,950 cases and 3,872 controls explored the correlation of rs383362 G>T with malignant tumor risk. 18 , 20 – 22 The genotyping methods used to detect the WWOX polymorphisms included sequencing, MassARRAY ® System (Agena Bioscience, Inc., San Diego, CA, USA), polymerase chain reaction-restriction fragment polymorphism (PCR-RFLP), and TaqMan ® (Thermo Fisher Scientific, Waltham, MA, USA). Furthermore, we divided them into population-based group or hospital-based group in all studies to distinguish between different sources of control group.…”

Section: Resultsmentioning

confidence: 99%

“…For the WWOX rs3764340 polymorphism, the studies consisted of three population-based controls 16 , 17 , 21 and five hospital-based controls. 15 , 18 – 20 , 22 For rs12918952 G>A and rs383362 G>T, one population-based control 21 and three hospital-based controls 18 , 20 , 22 were included in these studies, respectively. We used subgroup analyses to explore the effects of different sources of control and genotyping methods on the associations of increased risk of tumor with the WWOX rs3764340 C>G, rs12918952 G>A, and rs383362 G>T polymorphisms.…”

Section: Resultsmentioning

confidence: 99%

“… 15 – 20 However, other studies indicated that there were no significant associations. 21 , 22 Because of relatively small sample sizes, these studies provided limited evidence and might have been underpowered to detect the overall effects. Therefore, we conducted this study to obtain a more precise estimation from all eligible case–control studies.…”

Section: Introductionmentioning

confidence: 99%

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Association between WWOX and the risk of malignant tumor, especially among Asians: evidence from a meta-analysis

Hao

Zhang

et al. 2018

OTT

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PurposeMany studies have been carried out to examine whether there are associations between WWOX polymorphisms (rs3764340 C>G, rs12918952 G>A, and rs383362 G>T) and malignant tumor risk, but the results from these studies remained inconsistent and even controversial. In the present study, we performed a meta-analysis to evaluate the relationships comprehensively.MethodsPublished reports were searched in PubMed, Google Scholar, and Chinese National Knowledge Infrastructure databases. Eight eligible case–control studies were included in the final analysis. In the analysis, pooled odds ratios (ORs) with corresponding 95% CIs were calculated in five genetic models to assess the genetic risk. Egger’s regression and Begg’s funnel plots test were conducted to appraise the publication bias.ResultsWe found that rs12918952 G>A and rs383362 G>T polymorphisms were not associated with the susceptibility of malignant tumor. However, a significant correlation was found between WWOX rs3764340 C>G and malignant tumor risk in three genetic models (CG vs CC: OR=1.31, 95% CI: 1.12–1.53, P=0.031; GG/CG vs CC: OR=1.31, 95% CI: 1.11–1.54, P=0.014; G vs C: OR=1.28, 95% CI: 1.09–1.50, P=0.009). Furthermore, when stratified by source of control, the results were significant especially in population-based control for rs3764340.ConclusionIn general, our results first indicated that the rs3764340 C>G polymorphism in WWOX gene can increase the susceptibility of tumor, while the others cannot. However, large, well-designed epidemiological studies are required to verify our findings.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association between WWOX and the risk of malignant tumor, especially among Asians: evidence from a meta-analysis

Hao

Zhang

et al. 2018

OTT

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“…Considering the significant potential of WWOX in tumorigenesis and development, genetic variations within this gene are believed to affect the progression of tumor. But disappointedly, studies exploring the relationship between WWOX gene polymorphisms and tumor recurrence or HCC clinical outcome are very limited 17 , 18 . To test this hypothesis, 8 HCC patients with early tumor recurrence and 8 patients without recurrence were selected randomly for genotype analysis in order to identify potential SNPs between these two groups and subsquently to determine whether those candidate SNPs may be associated with clinical outcome in another group of 136 patients after curative resection.…”

Section: Introductionmentioning

confidence: 99%

Association of WWOX rs9926344 polymorphism with poor prognosis of hepatocellular carcinoma

Chen¹,

Zhou²,

Zhang³

et al. 2018

J. Cancer

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Introduction: The WW domain-containing oxidoreductase (WWOX), widely expressed in human tissues, is considered as a tumor suppressor gene and plays an important role in the incidence and progression of human cancer, HCC included. This study was to investigate the correlation between single nucleotide polymorphisms (SNPs) of the WWOX gene and the prognosis of hepatocellular carcinoma (HCC) patients.Materials and Methods: After a total of 152 HCC patients were recruited, 8 cases with tumor recurrence within 2-years after operation and 8 cases without recurrence were selected randomly for SNP genotyping and screening using Affymetrix Array 6.0. And then we confirmed candidate SNPs in the remaining 136 patients by time-of-flight mass spectrometry (TOF-MS).Results: In total, 32 SNPs were screened and identified as candidate SNPs with one SNP in particular, (rs9926344), being further verified to be valuable. We found that AA+AG genotype and A allele of WWOX rs9926344 were significantly associated with recurrent risk of HCC (p=0.002 and p=0.001, respectively). The Kaplan-Meier curve showed that patients carrying rs9926344 AA +AG genotype had poor RFS (P=0.004) and OS (P=0.005) compared to those carrying GG genotypes. The multivariate COX regression analysis showed that the AA+AG genotype were an independent prognostic factor for tumor recurrence (HR 1.787, 95% CI 1.042-3.064, P=0.035). Furthermore, IHC analysis showed that the WWOX protein down-regulation is more frequent in patients with AG genotype compared to those with GG genotype (P=0.023).Conclusion: Our findings indicate that WWOX rs9926344 polymorphism is positively correlated with tumor recurrence and can be used as an independent prognostic marker for HCC patients after operation.

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Low expression of WW domain‐containing oxidoreductase associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection

et al. 2018

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WW domain‐containing oxidoreductase (WWOX), which has a protein‐interaction domain and is regarded to be a tumor suppressor, has been known to play an important role in anti‐angiogenesis and cancer progression. This study aimed to investigate prognostic values of WWOX expression in hepatocellular carcinoma (HCC) patients after hepatectomy. Additionally, we intended to formulate a valuable prognostic nomogram for HCCs. 182 HCC patients who underwent hepatectomy from January 2009 to January 2010 were enrolled in our study. qRT‐PCR, Western blot, and immunohistochemistry on tissue microarrays were then used to determine the expression levels of WWOX. An evaluation of the role of WWOX expression levels in the prognosis and outcome of patients was established. A decrease in the expression of WWOX was found when compared to adjacent tumor‐free tissues, which led to worse overall survival (OS) and recurrence‐free survival (RFS) and, therefore, was considered as an independent negative factor in the prognosis of HCC. Two nomograms, comprising WWOX, alpha‐fetoprotein (AFP), tumor size, and γ‐glutamyltransferase (γ‐GT), were constructed to obtain superior discriminatory abilities than conventional staging systems in terms of C‐index and clinical net benefit on decision curve analysis (DCA) for OS and RFS. Our data suggest that WWOX expression is strongly related to HCC post‐resection aggressiveness and recurrence. Additional advanced and accurate predictive model through the incorporation of WWOX into nomogram could help predict OS or RFS for HCC patients.

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Functional genetic variant of WW domain-containing oxidoreductase (WWOX) gene is associated with hepatocellular carcinoma risk

Cited by 19 publications

References 63 publications

Association between WWOX and the risk of malignant tumor, especially among Asians: evidence from a meta-analysis

Association between WWOX and the risk of malignant tumor, especially among Asians: evidence from a meta-analysis

Association of WWOX rs9926344 polymorphism with poor prognosis of hepatocellular carcinoma

Low expression of WW domain‐containing oxidoreductase associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection

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