Association between leukocyte telomere length and glioma risk: a case-control study

Background

Compelling epidemiological evidence indicates that alterations of telomere length are associated with risks of many malignancies in a tumor-specific manner, such as lung cancer, breast cancer, and non-Hodgkin''s lymphoma. However, the association between leukocyte telomere length and glioma risk has not been investigated.

Methods

Relative telomere length (RTL) of peripheral blood leukocytes from 467 glioma patients and 467 healthy controls, matched by age and sex, was measured using the real-time PCR-based method in a case-control study. An unconditional multivariate logistic regression model was applied to estimate the association between RTL and glioma risk.

Results

Glioma patients showed notably longer RTL than controls (median, 0.555 vs 0.444; P > .04). RTL was negatively correlated with age in both cases (ρ = −0.430; P < .001) and controls (ρ = −0.388; P < .001). After adjusting for age, sex, smoking status and family history of cancer, multivariate logistic regression analysis showed that there was a U-shaped association between RTL and glioma risk (P for nonlinearity <.001). Compared with individuals in the second tertile of RTL, the odds ratios (95% CI) for participants in the first and third tertiles were 2.16 (range, 1.52–3.09) and 3.51 (range, 2.45–5.00), respectively. Stratified analysis showed that the association between RTL and glioma risk was not modulated by major host characteristics.

Conclusions

Our study demonstrates for the first time that either shorter or longer RTL in peripheral blood leukocytes is associated with increased glioma risk, which warrants further investigation in the future.     

Food groups and risk of hepatocellular carcinoma: A multicenter case-control study in Italy

The role of diet, except for alcohol drinking and aflatoxin contamination, in the etiology of hepatocellular carcinoma (HCC) is unclear. A hospital-based case-control study was conducted in Italy in 1999-2002, including 185 incident, histologically-confirmed cases of HCC. Controls were 412 subjects admitted to hospitals for acute, nonneoplastic diseases unrelated to diet. Dietary habits were assessed using a validated food-frequency questionnaire. Odds ratios (ORs) and the corresponding 95% confidence intervals (CI) were computed using unconditional multiple logistic regression, adjusting for hepatitis B (HBV) and hepatitis C (HCV) virus infection and alcohol drinking. Energy adjustment was carried out by means of the residual model. A significant inverse relation was found between intakes of milk and yoghurt (OR = 0.28; 95% CI: 0.13-0.61), white meats (OR = 0.44; 95% CI: 0.20-0.95), eggs (OR = 0.31; 95% CI: 0.14-0.69), and fruits (OR = 0.48; 95% CI: 0.22-1.05) and HCC risk. The favourable effect of high intakes of milk and yoghurt, white meats, eggs and fruits was consistent across strata of HBV and HCV infections. The present study supports the hypothesis of a role of diet in HCC aetiology. Dietary modifications may be indicated in subjects at high-risk for HCC.     

Association between mitochondrial DNA content in leukocytes and colorectal cancer risk: a case-control analysis

BACKGROUND:

Compelling epidemiological evidence indicated that alterations of mitochondrial DNA (mtDNA), including mutations and abnormal content of mtDNA, were implicated in the tumorigenesis of several malignancies in a tumor‐specific manner, such as lung cancer, breast cancer, and non‐Hodgkin lymphoma. This study was undertaken to investigate whether mtDNA content in peripheral blood lymphocytes (PBLs) could be used as a risk predictor for colorectal cancer (CRC).

METHODS:

The mtDNA content was measured by using quantitative real‐time polymerase chain reaction in PBLs from 320 CRC patients and 320 matched controls.

RESULTS:

The authors found that CRC patients exhibited statistically significantly higher mtDNA content than matched controls (median, 1.03 vs .86; P < .001). They further assessed the association between mtDNA content and CRC risk using multivariate logistic regression. By using the median value in controls as the cutoff point, they found that, compared with low mtDNA content, high mtDNA content was associated with a significantly increased CRC risk (adjusted odds ratio, 2.03; 95% confidence interval, 1.41‐2.81). In a trend analysis, they found a statistically significant dose‐response relationship between higher mtDNA content and increased CRC risk (P for trend <.001). Stratified analysis showed that the association between mtDNA content and CRC risk was not modulated by major host characteristics.

CONCLUSIONS:

These findings provide the first epidemiological evidence linking the high mtDNA content in PBLs to elevated CRC risk. Cancer 2011. © 2011 American Cancer Society.     

外周血白细胞端粒相对长度与噪声性听力损失的相关性研究

目的：探讨外周血白细胞端粒相对长度与噪声性听力损失（NIHL）的相关性。方法：用SV104IS无线个体噪声剂量计对某电脑机箱外壳制造企业所有作业岗位进行噪声强度检测,选择噪声强度超标[L_{EX,8 h} ≥ 85 dB（A）]生产岗位的全体生产工人作为研究对象。采用问卷调查法获得研究对象的一般情况和职业史,实时荧光定量PCR检测研究对象外周血白细胞端粒相对长度,有序多分类Logistic回归法分析外周血白细胞端粒相对长度与噪声性听力损失（NIHL）的相关性。结果：该企业噪声超标作业岗位噪声强度（L_{EX,8 h}）均值为（91.30±3.22） dB（A）。本次研究共调查127名噪声作业者：双耳听力正常43人（33.86%）,双耳高频听阈提高75人（59.06%）,单耳或双耳语频听阈提高伴双耳高频提高9人（7.09%）。不同NIHL程度工人的端粒相对长度差异有统计学意义（P < 0.05）。有序多分类Logistic回归分析显示,噪声强度、年龄、端粒相对长度、性别是NIHL的影响因素（P < 0.05）。结论：外周血白细胞端粒长度可能是发生NIHL的易感性生物标志物。     

Circulating leukocyte telomere length and risk of overall and aggressive prostate cancer

Background:

Recent large-scale prospective studies suggest that long telomeres are associated with an increase cancer risk, counter to conventional wisdom.

Methods:

To further clarify the association between leukocyte telomere length (LTL) and prostate cancer, and assess genetic variability in relation to both LTL and prostate cancer, we performed a nested case–control study (922 cases and 935 controls). The participants provided blood in 1993–1995 and were followed through August 2004 (prostate cancer incidence) or until 28 February 2013 (lethal or fatal prostate cancer). Relative LTL was measured by quantitative PCR and was calculated as the ratio of telomere repeat copy number to a single gene (36B4) copy number (T/S). Genotyping was performed using the TaqMan OpenArray SNP Genotyping Platform. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of all prostate cancer and subtypes defined by Gleason grade, stage and lethality (metastasis or death).

Results:

We observed a positive association between each s.d. increase in LTL and all (multivariable-adjusted OR 1.11, 95% CI: 1.01–1.22), low-grade (OR 1.13, 95% CI:1.01–1.27), and localised (OR 1.12, 95% CI:1.01–1.24) prostate cancer. Associations for other subtypes were similar, but did not reach statistical significance. In subgroup analyses, associations for high grade and advanced stage (OR=2.04, 95% CI 1.00–4.17; P_interaction=0.06) or lethal disease (OR=2.37, 95% CI 1.19–4.72; P_interaction=0.01) were stronger in men with a family history of the disease compared with those without. The minor allele of SNP, rs7726159, which has previously been shown to be positively associated with LTL, showed an inverse association with all prostate cancer risk after correction for multiple testing (P=0.0005).

Conclusion:

In this prospective study, longer LTL was modestly associated with higher risk of prostate cancer. A stronger association for more aggressive cancer in men with a family history of the disease needs to be confirmed in larger studies.     

Coffee and tea consumption and risk of hepatocellular carcinoma in Italy

The role of coffee in the aetiology of hepatocellular carcinoma has raised great interest. In Italy, coffee consumption is high, thus allowing the investigation of the topic over a broad range of consumption. A hospital-based case-control study was conducted in Italy in 1999-2002, including 185 incidents, histologically confirmed cases of hepatocellular carcinoma aged 43-84 years. Controls were 412 subjects admitted to the same hospitals' networks for acute, non-neoplastic diseases unrelated to diet. Coffee and tea consumption were assessed using a validated food-frequency questionnaire. Odds ratios (ORs) and corresponding the 95% confidence intervals (CI) were computed using unconditional multiple logistic regression, adjusting for hepatitis viruses seropositivity, alcohol intake, smoking habits and other potential confounding factors. Compared to people who drunk <14 cups/week of coffee, the risk of hepatocellular carcinoma decreased for increasing levels of consumption (OR=0.4, 95% CI: 0.2-1.1 for >or=28 cups/week, p for trend = 0.02). In the present study, inverse relations were observed across strata of hepatitis C and, B virus infections and alcohol drinking. No significant association emerged with consumption of decaffeinated coffee (OR=0.7, 95% CI=0.2-2.5) or tea (OR=1.4, 95% CI=0.8-2.7). The present study supports the hypothesis of a favourable effect of coffee, though not decaffeinated coffee and tea, on the risk on hepatocellular carcinoma.     

Noncoding telomeric repeat‐containing RNA inhibits the progression of hepatocellular carcinoma by regulating telomerase‐mediated telomere length

Telomeric repeat‐containing RNA (TERRA) is closely involved in the regulation of telomere length, which plays critical roles in tumorigenesis. However, the biological significance of TERRA in hepatocellular carcinoma (HCC) remains largely unknown. In this study, we found that HCC cells show a frequent downregulation of TERRA and its positive regulator TTAGGG repeat binding factor‐1 (TRF1), whereas the negative regulator TTAGGG repeat binding factor‐1 (TRF2) was upregulated. We found that TERRA, TRF1, and TRF2 contributed to poor prognosis of HCC patients. Importantly, we found that the downregulation of TERRA significantly promoted HCC cell growth and metastasis in vitro and in vivo, whereas the upregulation of TERRA showed an opposite effect. Mechanistically, downregulation of TERRA significantly increased telomerase activity and promoted telomere elongation. Moreover, the inhibitory effects of TERRA overexpression on the growth and metastasis of HCC cells were reversed by treatment with TA‐65 that activates telomerase activity. In contrast, the protumor effect of TERRA downregulation was reversed by treatment with TMPyP4 that inhibits telomerase activity. Our findings reveal that TERRA plays a critical role in HCC cell growth and metastasis, indicating that TERRA is a potential therapeutic target for HCC.     

Risk of renal cell carcinoma in relation to blood telomere length in a population-based case-control study

Background:

There are few known risk factors for renal cell carcinoma (RCC). Two small hospital-based case–control studies suggested an association between short blood telomere length (TL) and increased RCC risk.

Methods:

We conducted a large population-based case–control study in two metropolitan regions of the United States comparing relative TL in DNA derived from peripheral blood samples from 891 RCC cases and 894 controls. Odds ratios and 95% confidence intervals were estimated using unconditional logistic regression in both unadjusted and adjusted models.

Results:

Median TL was 0.85 for both cases and controls (P=0.40), and no differences in RCC risk by quartiles of TL were observed. Results of analyses stratified by age, sex, race, tumour stage, and time from RCC diagnosis to blood collection were similarly null. In multivariate analyses among controls, increasing age and history of hypertension were associated with shorter TL (P<0.001 and P=0.07, respectively), and African Americans had longer TL than Caucasians (P<0.001).

Conclusion:

These data do not support the hypothesis that blood TL is associated with RCC. This population-based case–control study is, to our knowledge, the largest investigation to date of TL and RCC.     

Nonreceptor protein tyrosine phosphatases (NRPTPs) gene family associates with the risk of hepatocellular carcinoma in a Chinese hepatitis B virus-related subjects

Nonreceptor protein tyrosine phosphatases (NRPTPs) are reported to be associated with several human cancers, but their roles in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unclear. Here, we integrated bioinformatics tools, population association analyses, and biological assays to systematically screen for potentially functional single nucleotide polymorphisms (SNPs) within the 17 NRPTPs genes and evaluate the effects of candidate SNPs on the risk of HCC or persistent HBV infection. A total of 790 HBV-related HCC cases and 1454 cancer-free controls were enrolled. Controls included 711 HBV persistent carriers and 743 spontaneously recovered subjects. Results demonstrated that PTPN4 rs9308777 (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.06-1.49, P = .009) and PTPN12 rs350050 (OR = 1.26, 95% CI = 1.10-1.45, P = .001), were significantly associated with HCC risk, but not with persistent HBV infection risk. The cumulative risk effect of these two SNPs was more significantly increased the susceptibility to HCC (OR = 1.27, 95% CI = 1.14-1.41, P = 2.40 × 10⁻⁵). Subsequent biological assays further revealed the potential pathogenesis that PTPN4 rs9308777 might decrease the gene expression, and PTPN12 rs3750050 might promote cell proliferation by attenuating PTPN12's inhibitory activity on EGFR/ERK pathway. In summary, our integrative study highlights that PTPN4 and PTPN12 are significantly associated with HBV-related HCC risk, but do not influence persistent HBV infection. These findings shed light on the importance of the synergistic effects of regulatory and missense variants on the risk for HCC, and provide data to support personalized cancer medicine in the future.     

Type 2 diabetes and hepatocellular carcinoma: a case-control study in patients with chronic hepatitis B

Type 2 diabetes has been suggested as an independent risk factor for the development of hepatocellular carcinoma (HCC). However, the role of Type 2 diabetes on the development of HCC in the presence of chronic hepatitis B (CHB) remains inconclusive. We conducted this hospital-based case-control study to evaluate the roles of Type 2 diabetes in HCC development in patients with CHB. From January 2004 to December 2008, a total of 6,275 eligible consecutive patients with chronic hepatitis B virus (HBV) infection were recruited. A total of 1,105 of them were patients with HBV-related HCC and 5,170 patients were CHB but without HCC. We used multivariate logistic regression models to investigate the association between Type 2 diabetes and HCC risk. The prevalence of Type 2 diabetes is higher among HCC patients without cirrhosis than among those with cirrhosis (12.1% vs. 6.7%, p=0.003). Type 2 diabetes was associated with a significantly high risk of HCC in female patients after adjusting for age, family history of HCC, city of residence, hepatitis B e antigen and cirrhosis with an odds ratio (95% confidence interval, CI) of 1.9 (1.1-3.4). Restricted analyses among female patients without cirrhosis indicated that Type 2 diabetes was strongly associated with HCC risk with adjusted odds ratio (95% CI) of 5.6 (2.2-14.1). In conclusion, Type 2 diabetes is independently associated with the increased risk of HCC in female CHB patients. Female CHB patients with Type 2 diabetes are of a high HCC risk population and should be considered for HCC close surveillance program.     

Long telomeres in peripheral blood leukocytes are associated with an increased risk of soft tissue sarcoma

BACKGROUND:

Human telomeres consisting of long, tandem repeats of the nucleotide sequence TTAGGG at the chromosome ends are essential for maintaining chromosomal stability. Previous epidemiologic studies have indicated that shorter telomere length in peripheral blood leukocytes (PBLs) is associated with the development of many cancers. However, the relation between PBL telomere length and the risk of soft tissue sarcoma (STS) has not been investigated.

METHODS:

The relative telomere length (RTL) was determined in PBLs using real‐time polymerase chain reaction in this case‐control study. The study participants included 137 patients with histologically confirmed STS (cases) who had received no prior chemotherapy or radiotherapy and 137 healthy controls who were frequency‐matched to cases on age, sex, and ethnicity.

RESULTS:

Patients in the case group had significantly longer RTL than controls (1.46 ± 0.42 for cases vs 1.15 ± 0.39 for controls; P < .001). By using median RTL in the controls as a cutoff level, individuals who had long telomere length were associated with a significantly increased risk of STS compared with those who had short telomere length (adjusted odds ratio, 4.71; 95% confidence interval, 2.63‐8.44). When participants were categorized further into 3 or 4 groups according to the tertile or quartile RTL values of healthy controls, a significant dose‐response relation was observed between longer RTL and increased risks of STS.

CONCLUSIONS:

The current results provided the first epidemiologic evidence that longer telomere length in PBLs is associated significantly with an increased risk of STS, potentially suggesting an important role for telomere maintenance in STS development. Cancer 2013. © 2013 American Cancer Society.     

Quantitative evaluation of hepatitis B virus mutations and hepatocellular carcinoma risk: a meta-analysis of prospective studies

Background

The temporal relationship between hepatitis B virus (HBV) mutations and hepatocellular carcinoma (HCC) remains unclear.

Methods

We conducted a meta-analysis including cohort and nested case-control studies to prospectively examine the HCC risk associated with common variants of HBV in the PreS, Enhancer II, basal core promoter (BCP) and precore regions. Pertinent studies were identified by searching PubMed, Web of Science and the Chinese Biological Medicine databases through to November 2014. Study-specific risk estimates were combined using fixed or random effects models depending on whether significant heterogeneity was detected.

Results

Twenty prospective studies were identified, which included 8 cohort and 12 nested case-control studies. There was an increased risk of HCC associated with any PreS mutations with a pooled relative risk (RR) of 3.82 [95% confidence interval (CI): 2.59-5.61]. The pooled-RR for PreS deletion was 3.98 (95% CI: 2.28-6.95), which was higher than that of PreS2 start codon mutation (pooled-RR=2.63, 95% CI: 1.30-5.34). C1653T in Enhancer II was significantly associated with HCC risk (pooled-RR=1.83; 95% CI: 1.21-2.76). For mutations in BCP, statistically significant pooled-RRs of HCC were obtained for T1753V (pooled-RR=2.09; 95% CI: 1.49-2.94) and A1762T/G1764A double mutations (pooled-RR=3.11; 95% CI: 2.08-4.64). No statistically significant association with HCC risk was observed for G1896A in the precore region (pooled-RR=0.77; 95% CI: 0.47-1.26).

Conclusions

This study demonstrated that PreS mutations, C1653T, T1753V, and A1762T/G1764A, were associated with an increased risk of HCC. Clinical practices concerning the HCC risk prediction and diagnosis may wish to focus on patients with these mutations.     

Betel quid chewing as a risk factor for hepatocellular carcinoma: a case-control study

The role of betel quid chewing in the aetiology of hepatocellular carcinoma (HCC) was evaluated in a case-control study including 263 pairs of age- and sex-matched HCC patients and healthy controls. Serum hepatitis B surface antigen (HBsAg), and antibodies to hepatitis C virus (anti-HCV) were determined, and standardized personal interview conducted using a structured questionnaire. Multivariate analysis indicated that betel quid chewing (odds ratio (OR), 3.49; 95% confidence interval (CI), 1.74-6.96), HBsAg (OR, 16.69; 95% CI, 9.92-28.07), anti-HCV (OR, 38.57; 95% CI, 18.15-81.96), and educational duration of less than 10 years (OR, 1.71; 95% CI, 1.05-2.78) are independent risk factors of HCC. In addition, there was an additive interaction between betel quid chewing and chronic infection with either hepatitis B virus (synergy index, 5.37) or hepatitis C virus (synergy index, 1.66). Moreover, risk on HCC increased as duration of betel quid chewing increased, or amount of betel quid consumed (each P for trend < 0.0001).     

Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men.

BACKGROUND: The incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is higher in men than in women. We examined whether endogenous sex hormone levels or hormone-related factors might affect the risk of HCC in men. METHODS: Baseline blood samples were collected from 4841 male Taiwanese HBV carriers without diagnosed HCC from 1988 through 1992. Plasma testosterone and estradiol levels and genetic polymorphisms in the hormone-related factors cytochrome P450c17 alpha (CYP17, A1 versus A2 alleles), steroid 5 alpha-reductase type II (SRD5A2, valine [V] versus leucine [L] alleles), and androgen receptor (AR, number of CAG repeats) were assayed among 119 case patients who were diagnosed with HCC during 12 years of follow-up and 238 control subjects. All statistical tests were two-sided. RESULTS: The risk of HCC increased with increasing concentrations of testosterone (odds ratio [OR](highest versus lowest tertile) = 2.97; 95% confidence interval [CI] = 1.54 to 5.70; P(trend) <.001) and with increasing number of the V allele of the SRD5A2 V89L polymorphism (OR(VV versus LL genotype) = 2.47; 95% CI = 1.21 to 5.03; P(trend) =.011). Fewer AR gene CAG repeats (<23 repeats) were associated with a 1.64-fold (95% CI = 1.00 to 2.68) increased risk of HCC. Although the CYP17 genotype alone did not increase the risk of HCC, there was evidence of a gene-gene interaction, because the CYP17 A1 allele statistically significantly increased the risk of HCC in the presence of fewer AR gene CAG repeats (OR = 2.51; 95% CI = 1.06 to 5.94). We found a similar interaction between the SRD5A2 VV genotype and fewer AR gene CAG repeats (OR = 5.58; 95% CI = 1.86 to 16.71). Body mass index (BMI) modified the association of HCC with testosterone and SRD5A2 genotype; in men with low BMI, multivariate-adjusted ORs for the highest tertile of testosterone versus the lowest and the SRD5A2 VV genotype versus the LL genotype were 7.63 (95% CI = 2.13 to 27.27) and 8.64 (95% CI = 2.75 to 27.14), respectively. No clear associations were found between estradiol or testosterone-to-estradiol ratio and HCC. CONCLUSIONS: Pathways involving androgen signaling may affect the risk of HBV-related HCC among men.     

Plasma circular RNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma: A large-scale,multicenter study

To explore whether plasma circular RNAs (circRNAs) can diagnose hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), microarray and qPCR were used to identify plasma circRNAs that were increased in HBV-related HCC patients compared to controls (including healthy controls, chronic hepatitis B and HBV-related liver cirrhosis). A logistic regression model was constructed using a training set (n = 313) and then validated using another two independent sets (n = 306 and 526, respectively). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. We identified a plasma circRNA panel (CircPanel) containing three circRNAs (hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) that could detect HCC. CircPanel showed a higher accuracy than AFP (alpha-fetoprotein) to distinguish individuals with HCC from controls in all three sets (AUC, 0.863 [95% confidence interval, CI: 0.819–0.907] vs. 0.790 [0.738–0.842], p = 0.036 in training set; 0.843 [0.796–0.890] vs. 0.747 [0.691–0.804], p = 0.011 in validation set 1 and 0.864 [0.830–0.898] vs. 0.769 [0.728–0.810], p < 0.001 in validation set 2). CircPanel also performed well in detecting Small-HCC (solitary, ≤3 cm), AFP-negative HCC and AFP-negative Small-HCC.     

Fluid consumption and the risk of bladder cancer: results of a multicenter case-control study

A number of studies suggest a relation between fluid consumption and the risk of bladder cancer but results are contradictory. Different theories involving the quantity or the type of fluid consumed have been put forward to explain these relations but mechanisms remain unclear. We conducted a multicenter case-control study in several hospitals in France including 765 cases and 765 matched controls. Information collected by face-to-face interview included quantity and type of beverages consumed from the age of 18 until age at diagnosis, as well as smoking habits. Among men, we observed a slight non-significant increased risk of bladder cancer associated with total fluid intake, irrespectively of tobacco use. This was essentially due to intake of non-alcoholic drinks, coffee and bottled juice or water. Relative risks greater than 1 were observed in relation with coffee consumption. On the other hand, alcohol consumption, especially wine, was associated with relative risks less than unity. No relation could be identified between bladder cancer risk and fluid consumption among women. Our results do not support an association between total fluid consumption and bladder cancer risk. The role of the different types of fluid consumed, confounding factors and bias in the present analysis are discussed.     

Coinfection of hepatitis B and C viruses and risk of hepatocellular carcinoma: Systematic review and meta‐analysis

A subadditive effect of hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is possible because superinfection of one virus tends to inhibit infection of the other virus. However, studies have reported inconsistent findings, and two meta‐analyses of studies from various countries (1998) and China (2005) reported a supraadditive effect for hepatocellular carcinoma (HCC) risk. Thus, we reevaluate HBV/HCV monoinfection and coinfection. Of 411 reports, we included 59 studies that assessed the association between HBV/HCV monoinfection and coinfection for HCC risk. HCC risk because of high/detectable HBV DNA and HBeAg infection was higher than HBsAg infection, whereas anti‐HCV vs anti‐HCV/HCV RNA was not different. Geographically, HCC risk was significantly higher in nonendemic than in HBV or HCV endemic areas. Subadditive effect for HCC risk was presented in recently published studies, cohort studies and studies conducted in HBV/HCV nonendemic areas; an additive effect was presented in studies conducted in HBV endemic areas; a supraadditive effect was presented in previously published studies, case‐control studies and studies conducted in HCV endemic areas. Our results suggest HBV/HCV coinfection for HCC risk is not significantly greater than HBV/HCV monoinfection, and HCC risk due to HBV or HCV is higher in nonendemic than endemic areas. The p‐heterogeneity was significant for most analyses, except HBV(+)/HCV(+) and HBV biomarker analyses. Prevention strategies targeted toward HBV or HCV monoinfected patients are needed. In addition, tailored prevention to reduce infectivity such as HBV markers (HBeAg, HBV DNA) is needed.