Hepatocellular Carcinoma In Asians Research Articles

Association between antihypertensive drugs and hepatocellular carcinoma: A trans-ancestry and drug-target Mendelian randomization study.

Antihypertensive drugs were recently reported to have an oncogenic role in common cancer, however, whether these drugs would affect the risk of hepatocellular carcinoma (HCC) remains unclear. A drug-target Mendelian randomization method was adopted to examine the long-term effect of 12 antihypertensive drugs classes on the risk of HCC in Europeans and East Asians. To proxy antihypertensive drugs, we leveraged genetic variants located near or within drug target genes that were associated with systolic blood pressure (SBP). Genetically proxied drugs associated with reduced risk of coronary artery disease were included in primary analysis. Genetic summary statistics of SBP and HCC were derived from publicly available large-scale genome-wide association studies in Europeans and East Asians respectively. Expression quantitative trait loci (eQTLs) of drugs target genes were used to proxy drugs in a sensitivity analysis. Genetically proxied thiazides and related diuretics were associated with decreased risk of HCC in both Europeans (OR [95% CI]: 0.79 [0.73, 0.86] per 1 mmHg reduction in SBP; p < 0.001) and East Asians (0.60 [0.45, 0.82]; p = 0.001). Genetically proxied beta-adrenoceptor blockers (BBs) were strongly associated with increased risk of HCC in Europeans (1.46 [1.12, 1.91]; p = 0.004). These findings were replicated in deCODE genetics study and remained consistent when using eQTLs to proxy antihypertensive drugs. Our findings suggested that thiazides diuretics may lower the risk of HCC in both Europeans and East Asians, while BBs may increase the risk of HCC specifically in Europeans. Further studies are warranted to explore the potential of repurposing or retargeting antihypertensive drugs for HCC prevention.

Abstract PO-194: Hepatocellular carcinoma disparities among Latinos: A systematic literature review

Abstract Background: Liver cancer is one of the most important cancers in the United States, and hepatocellular carcinoma (HCC) is its most common form. In addition, health disparities can impact cancer-related outcomes in racial/ethnic minorities. Therefore, the aim of this study was to conduct a systematic review to analyze the hepatocellular carcinoma disparities among Latinos. Methods: A systematic review was conducted following the PRISMA guidelines. Papers were selected searching PubMed/Medline, SciELO, and LILACS databases in July 2021 using the search terms [Latin Americans] OR [Latinos] OR [Hispanics] OR [Racial Disparity] AND [Hepatocellular carcinoma]. The inclusion criteria was limited to observational studies published in the last five years that evaluated hepatocellular carcinoma disparities among Hispanics/Latinos. The language was restricted to English, Spanish or Portuguese. Results: Among the 179 papers initially identified, 44 were eligible for this review after full texts were read. Although there is a constant evolution in screening, diagnosis, and treatment strategies to improve the prognosis of HCC; racial and ethnic minorities are reported to have higher mortality related to HCC. In the United States, the age-adjusted incidence of HCC in Hispanics has surpassed those of HCC in Asians. From a public health perspective, active hepatitis C and B continue to drive most of the global burden of HCC, and there is a high prevalence of these infections in Latin America. In addition, non-alcoholic fatty liver disease (NAFLD) is one of the main risk factors for HCC in the USA, followed by alcoholic liver disease, and hepatitis C and B infections. Latin Americans have a higher prevalence of NAFLD, whereas African Americans have a lower prevalence of NAFLD. The exact contribution of genetic and environmental factors on these differences in prevalence has not been determined. While one in five HCC patients in the USA is of Hispanic ethnicity, only 38% meet the criteria for liver transplantation at the time of diagnosis. Acculturation, insurance status, and access to health care may further contribute to the observed HCC disparities among Latinos. Conclusions: The data indicates that HCC disparities in early diagnosis, treatment, and outcomes among Latinos are an important issue and need more attention. We suggest that interventions are necessary to reduce HCC disparities among Latinos in order to improve cancer-related outcomes. Citation Format: Tulio L. Correa, Mariana S.T.C. Guelli. Hepatocellular carcinoma disparities among Latinos: A systematic literature review [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-194.

Analyzing TCGA Data to Identify Gene Mutations Linked to Hepatocellular Carcinoma in Asians

Introduction: Liver cancer is the sixth most common and second most fatal type of cancer worldwide. Few treatment options are available as patients with liver cancer are often diagnosed in an advanced stage due to a lack of clinical symptoms. Effectively preventing and treating liver cancer relies heavily on early diagnosis; early diagnosis results from identifying and monitoring high-risk patients. Epigenetic risk factors, such as hepatitis B, hepatitis C, cirrhosis, nonalcoholic fatty liver disease, and alcohol/tobacco abuse, are highly prevalent in Asia and likely cause Asians to have a higher incidence and mortality rate of liver cancer. While these acquired risk factors are relatively well understood, the underlying genetic background of liver cancer in Asians has not been well established or correlated with clinical outcomes. Methods: In this study, we accessed The Cancer Genome Atlas (TCGA) hepatocellular carcinoma clinical and mutation data through TCGAbiolinksGUI. Results: We found that mutations in five genes (TP53, TTN, OBSCN, MUC5B, CSMD1) were statistically linked with increased mortality in Asians compared to non-Asians, four of which (TTN, OBSCN, MUC5B, CSMD1) were also more prevalent in the Asian population. Within the Asian cohort, two gene mutations (TTN, HMCN1) were statistically linked with worse outcomes. We also found that the TP53 mutation predicts worse outcomes within the non-Asian cohort but not within the Asian cohort. Discussion/Conclusion: Our findings can improve cancer care in the Asian population through better disease prognostication, evaluations for potential targeted therapy, and a deeper understanding of liver cancer pathogenesis.

Correlation Between MTHFR Polymorphisms and Hepatocellular Carcinoma: A Meta-analysis

The correlation between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and hepatocellular carcinoma (HCC) remains controversial. Therefore, we performed this study to better assess the relationship between MTHFR polymorphisms and the likelihood of HCC. A systematic research of PubMed, Medline, and Embase was performed to retrieve relevant articles. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A total of 15 studies with 8,378 participants were analyzed. In overall analyses, a significant association with the likelihood of HCC was detected for the rs1801131 polymorphism with fixed-effect models in recessive comparison (P = 0.002, OR = 0.62, 95% CI 0.43–0.82). However, no positive results were detected for the rs1801133 polymorphism in any comparison. Further subgroup analyses revealed that the rs1801131 polymorphism was significantly associated with the likelihood of HCC in Asians with both FEMs (recessive model: P < 0.0001, OR = 0.42, 95% CI 0.29–0.62; allele model: P = 0.004, OR =1.20, 95% CI 1.06–1.35) and random-effect models (recessive model: P = 0.002, OR = 0.47, 95% CI 0.29–0.75). Nevertheless, we failed to detect any significant correlation between the rs1801133 polymorphism and HCC. In conclusion, our findings indicated that the rs1801131 polymorphism may serve as a genetic biomarker of HCC in Asians.

Validation of the Toronto hepatocellular carcinoma risk index for patients with cirrhosis in China: a retrospective cohort study

BackgroundThe Toronto hepatocellular carcinoma (HCC) risk index (THRI) was developed to predict HCC in patients with cirrhosis. This study aimed to validate the THRI in a 10-year Asian cohort.MethodsA total of 2836 patients with cirrhosis at the First Affiliated Hospital of Soochow University between January 2008 and May 2018 were evaluated. Based on the THRI value at diagnosis, patients were divided into three groups (< 120, low-risk; 120–240, intermediate-risk; > 240, high-risk). Student’s t test and Fisher’s exact test were applied to compare parameters between the HCC group and the non-HCC group. The receiver operator characteristic (ROC) curve was drafted to identify the value of the THRI in predicting HCC. Logistic regression was utilized to assess the relationship between the development of HCC and THRI values. The incidence of HCC was calculated for the three groups using the Kaplan-Meier method, and curves were compared using the log-rank test.ResultsOf 520 patients enrolled in this study, 76 patients developed HCC. Patients who developed HCC had a higher THRI score than those who did not develop HCC (279.5 ± 57.1 vs. 232.3 ± 67.6, respectively, p < 0.001). The area under the ROC curve for the THRI to predict HCC was 0.707 ([95% CI 0.645–0.769], p < 0.001), with a sensitivity of 0.842 and a specificity of 0.486 when the cutoff THRI value was 226. Compared to the low-risk group, the high-risk group presented higher odds of developing HCC (adjusting odds ratio 1.026 [95% CI 1.002–1.051], p = 0.036). Differences existed in the cumulative incidence of HCC among the three risk groups (log-rank, p < 0.001). The 5-year cumulative HCC incidence of the low-risk group, intermediate-risk group, and high-risk group was 0%, 13%, and 34%, respectively.ConclusionThis study validated THRI values for predicting HCC in Asians with cirrhosis, which presented a fine sensitivity to identify the high-risk population of HCC for secondary prevention.

Epidemiology and Management of Hepatocellular Carcinoma

The major risk factors for hepatocellular carcinoma (HCC) in contemporary clinical practice are becoming increasingly related to sustained virological response after hepatitis C, suppressed hepatitis B virus during treatment, and alcoholic and nonalcoholic fatty liver disease. We review the emerging data on the risk and determinants of HCC in these conditions and the implications of HCC surveillance. However, from a public health perspective, active hepatitis C and B continue to drive most of the global burden of HCC. In United States, the age-adjusted incidence rates of HCC in Hispanics have surpassed those of HCC in Asians. Prognosis in HCC is complex because of the competing risk imposed by underlying cirrhosis and presence of malignancy. In addition to tumor burden, liver function and performance status; additional parameters including tumor biopsy, serum markers, and subclassification of current staging systems; and taking into account patterns of tumor progression may improve patient selection for therapy. Advancements in the treatment of HCC have included identification of patients who are most likely to derive a clinically significant benefit from the available therapeutic options. Additionally, the combination strategies of locoregional therapies and/or systemic therapy are being investigated.

Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy

Recently, the PAGE-B score and Toronto HCC risk index (THRI) have been developed to predict the risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB). We aimed to validate PAGE-B scores and THRI in Asian patients with CHB and suggested modified PAGE-B scores to improve the predictive performance. From 2007 to 2017, we examined 3,001 Asian patients with CHB receiving entecavir/tenofovir therapy. We assessed the performances of PAGE-B, THRI, CU-HCC, GAG-HCC, and REACH-B for HCC development. A modified PAGE-B score (mPAGE-B) was developed (derivation set, n = 2,001) based on multivariable Cox models. Bootstrap for internal validation and external validation (validation set, n = 1,000) were performed. The five-year cumulative HCC incidence rates were 6.6% and 7.2% in the derivation and validation datasets after entecavir/tenofovir onset. In the derivation dataset, age, gender, serum albumin levels, and platelet counts were independently associated with HCC. The mPAGE-B score was developed based on age, gender, platelet counts, and serum albumin levels (time-dependent area under receiver operating characteristic curves [AUROC] = 0.82). In the validation set, the PAGE-B and THRI showed similar AUROCs to CU-HCC, GAG-HCC, and REACH-B at five years (0.72 and 0.73 vs. 0.70, 0.71, and 0.61 respectively; all p >0.05 except REACH-B), whereas the AUROC of mPAGE-B at five years was 0.82, significantly higher than the five other models (all p <0.01). HCC incidence rates after initiation of entecavir/tenofovir therapy in patients with CHB were significantly decreased in all risk groups in long-term follow-up periods. Although PAGE-B and THRI are applicable in Asian patients with CHB receiving entecavir/tenofovir therapy, mPAGE-B scores including additional serum albumin levels showed better predictive performance than the PAGE-B score. PAGE-B scores and Toronto HCC risk index were developed to predict the risk of hepatocellular carcinoma (HCC) in Caucasian patients with CHB under potent antiviral therapy. This study validated these two scores in Asian patients with CHB and suggested that modified PAGE-B scores could improve the predictive performance. A modified PAGE-B score, which is based only on a patient's age, gender, baseline platelet counts, and serum albumin levels at treatment initiation, represents a reliable and easily available risk score to predict HCC development during the first five years of antiviral treatment in Asian patients with CHB. With a scoring range from 0 to 21 points, a modified PAGE-B score differentiates the HCC risk. A modified PAGE-B score significantly differentiates the five-year HCC risk: low ≤8 points and high ≥13 points.

FRI-274 - Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy

FRI-274 - Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy

Development of a scoring system to predict hepatocellular carcinoma in Asians on antivirals for chronic hepatitis B

The risk of hepatocellular carcinoma (HCC) during antiviral therapy in patients with chronic hepatitis B (CHB) is inadequately predicted by the scores built from untreated patients. We aimed at developing and validating a risk score to predict HCC in patients with CHB on entecavir or tenofovir treatment. This study analysed population-wide data from the healthcare databases in Taiwan and Hong Kong to identify patients with CHB continuously receiving entecavir or tenofovir. The development cohort included 23,851 patients from Taiwan; 596 (2.50%) of them developed HCC with a three-year cumulative incidence of 3.56% (95% CI 3.26-3.86%). The multivariable Cox proportional hazards model found that cirrhosis, age (cirrhosis and age interacted with each other), male sex, and diabetes mellitus were the risk determinants. These variables were weighted to develop the cirrhosis, age, male sex, and diabetes mellitus (CAMD) score ranging from 0 to 19 points. The score was externally validated in 19,321 patients from Hong Kong. The c indices for HCC in the development cohort were 0.83 (95% CI 0.81-0.84), 0.82 (95% CI 0.81-0.84), and 0.82 (95% CI 0.80-0.83) at the first, second, and third years of therapy, respectively. In the validation cohort, the c indices were 0.74 (95% CI 0.71-0.77), 0.75 (95% CI 0.73-0.78), and 0.75 (95% CI 0.72-0.77) during the first three years, and 0.76 (95% CI 0.74-0.78) and 0.76 (95% CI 0.74-0.77) in the extrapolated fourth and fifth years, respectively. The predicted and observed probabilities of HCC were calibrated in both cohorts. A score <8 and >13 points identified patients at distinctly low and high risks. The easily calculable CAMD score can predict HCC and may inform surveillance policy in patients with CHB during oral antiviral therapy. This study analyses population-wide data from the healthcare systems in Taiwan and Hong Kong to develop and validate a risk score that predicts hepatocellular carcinoma during oral antiviral therapy in patients with chronic hepatitis B. The easily calculable CAMD score requires only simple information (i.e. cirrhosis, age, male sex, and diabetes mellitus) at the baseline of treatment initiation. With a scoring range from 0 to 19 points, the CAMD score discriminates the risk of hepatocellular carcinoma with a concordance rate of around 75-80% during the first three years on therapy. The risk prediction can be extrapolated to five years on treatment with similar accuracy. Patients with a score <8 and >13 points were exposed to distinctly lower and higher risks, respectively.

Study of the association between five polymorphisms and risk of hepatocellular carcinoma: A meta-analysis

BackgroundRecently, several studies have investigated the association between polymorphisms in miR-146a rs2910164, miR-196a2 rs11614913, miR-499 rs3746444, miR-149 rs229283, miR-34b/c rs4938723, and hepatocellular carcinoma (HCC), which showed inconclusive results. MethodsA publication search was performed in PubMed, ExcerptaMedica Database, Chinese Biomedical Literature Database, and Chinese National Knowledge Infrastructure to collect relevant medical data published through February 2016. The aim of this study was to ascertain the association between HCC and micro-RNAs. A total of 21 studies were included in our study, which showed that miR-146a rs2910164 polymorphism has a significant association with HCC in the allele, recessive, and homozygous models overall [allele model: odds ratio (OR) = 0.927, 95% confidence interval (CI): 0.869–0.988, p = 0.02; recessive model: OR = 0.893, 95% CI: 0.814–0.981, p = 0.018; homozygous model: OR = 0.853, 95% CI: 0.744–0.978, p = 0.023] and in Asian populations (allele model: OR = 0.921, 95% CI: 0.863–0.983, p = 0.014; recessive model: OR = 0.893, 95% CI: 0.814–0.981, p = 0.019; homozygous model: OR = 0.851, 95% CI: 0.741–0.977, p = 0.022). For miR-196a2 rs11614913, significant statistical heterogeneity overall and in Asian populations was identified in the comparison of the allele, recessive, homozygous, and heterozygous models (overall: allele model: OR = 0.889, 95% CI: 0.842–0.94, p < 0.001; recessive model: OR = 0.837, 95% CI: 0.723–0.970, p = 0.018; homozygous model: OR = 0.722, 95%CI: 0.575–0.906, p = 0.005; heterozygous model: OR = 0.532, 95% CI: 0.37–0.765, p = 0.001), and also has a decreased risk of HCC in Caucasians in all genetic models except for the heterozygous model (allele model: OR = 0.658, 95% CI: 0.49–0.885, p = 0.006; dominant model: OR = 0.641, 95% CI: 0.418–0.981, p = 0.041; recessive model: OR = 0.489, 95% CI: 0.278–0.862, p = 0.013; homozygous model: OR = 0.414, 95% CI: 0.222–0.772, p = 0.005). Only the recessive models produced a significant association between miR-499 rs3746444 polymorphism and HCC risk (recessive model: OR = 1.283, 95% CI: 1.008–1.632, p = 0.043). ResultsThe analysis for miR-146a rs2910164 polymorphisms by racial decent found the same association between miR-146a rs2910164 polymorphism and susceptibility to HCC in Asians, but no significance risk association was observed in Caucasians. The meta-analysis results showed that miR-196a2 rs11614913 was associated with a decreased risk of HCC in Caucasians in all genetic models except for the heterozygous model. In the Asian population, miR-499 rs3746444 polymorphism was associated with a decreased risk of HCC in recessive models. This meta-analysis showed that no significant statistical heterogeneity was identified in miR-149 rs2292832 and miR-34b/c rs4938723. ConclusionOur findings supported the proposition that the polymorphisms of miR-146a rs2910164, miR-196a2 rs11614913, and miR-196a2 rs11614913 may contribute to the susceptibility of HCC.

Non-alcoholic Fatty Liver Disease in South Asians: A Review of the Literature.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are national and global epidemics. The disease is characterized by a spectrum of liver steatosis (fat deposition), inflammation (in NASH) and fibrosis. NAFLD and specifically NASH can lead to cirrhosis, which carry risks of progression to portal hypertension and hepatocellular carcinoma (HCC). NASH is also associated with higher mortality from cardiovascular causes. Most of the data for NAFLD has been obtained from the perspective of developed nations, although the disease is increasing and threatening to reach epidemic proportions across the world. Emerging data is notable for high prevalence of NAFLD in South Asian populations, presumably resulting from a combination of underlying genetic polymorphisms and changes in socio-economic status. It is also notable that an ‘Asian Paradox’ has been defined for NAFLD based upon the observation of lower than pre-defined body mass index (BMI), otherwise termed as “lean NAFLD”, among this population. Yet, data remains limited in regards to the characteristics of NAFLD/NASH in this population. In this article, we present a review of the literature and discuss the prevalence, associated risk factors and burden of HCC in South Asians with NAFLD.

RUNX3 promoter methylation correlation with pathogenesis of hepatocellular carcinoma in Asians

The aim of this study was to elucidate the role of RUNX3 promoter methylation in the pathogenesis of hepatocellular carcinoma (HCC) among Asians. For this purpose, we performed a comprehensive search of Chinese and English language scientific literature databases using stringent selection criteria; ultimately, we identified relevant studies that specifically assessed the correlation between RUNX3 promoter methylation and HCC. All data was retrieved and analyzed by two independent investigators using the STATA software (version 12.0). Initially, 132 studies (103 in Chinese, 29 in English) were retrieved; 122 were eliminated through a stepwise filtering process. Finally, 10 studies conducted in Asian populations (5 Chinese, 4 Japanese, 1 Korean) fulfilled all the inclusion criteria of our meta-analysis. The studies included 588 HCC patients (641 cancer tissues; 593 adjacent normal tissues) and 184 healthy controls. We observed that RUNX3 promoter methylation was significantly higher in cancer tissues than in adjacent normal tissues (RR = 6.35, 95%CI = 3.62-11.14, P < 0.001) and normal control tissues (RR = 17.31, 95%CI = 7.08-42.34, P < 0.001). RUNX3 promoter methylation status did not differ significantly between patients with different TNM stages (RR = 0.88, 95%CI = 0.70-1.10, P = 0.269) and histological grades (RR = 0.86, 95%CI = 0.65-1.14, P = 0.304), suggesting that RUNX3 promoter methylation is linked to the origin of HCC but not to its progression from non-metastatic to metastatic stages. This in turn indicated that RUNX3 could be an early diagnostic marker distinguishing benign from malignant hepatocellular carcinoma.

Association between the CYP1A1 polymorphisms and hepatocellular carcinoma: a meta-analysis.

Numerous studies have evaluated the association between CYP1A1 gene polymorphisms and hepatocellular carcinoma (HCC) risk. However, the specific association is still controversial. The aim of our study was to clarify the effects of CYP1A1 gene polymorphisms (3801 T＞C and A2455G) on HCC risk by conducting a meta-analysis. We conducted searches of the literature published in PubMed and EMBASE databases up to April 2014. We estimated the pooled odds ratio with its 95% confidence interval to assess the association using a fixed or random-effects model. Publication bias was investigated by the Begg funnel plot. Meta-analysis was performed using the STATA package version 12.0. Meta-analysis results showed no significant association between the CYP1A1 3801 T＞C polymorphism and HCC risk. In a subgroup analysis by nationality, we found a significant association between 3801 T＞C polymorphism and HCC risk in Asians (TT vs TC: OR = 0.77, 95%CI = 0.60-0.99). As for A2455G, the meta-analysis indicated no significant association between the CYP1A1 A2455G polymorphism and HCC risk. In conclusion, the 3801 T＞C polymorphism in the CYP1A1 gene may be related to increased risk of HCC in Asians. Conclusive evidence on the effects of the variants in HCC should be addressed in further studies.

Significant association between the MTHFR A1298C polymorphism and hepatocellular carcinoma risk: a meta-analysis.

The A1298C polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene has been reported to be associated with hepatocellular carcinoma (HCC), but there are conflicting results from previous studies. The present study aimed to investigate the association between this polymorphism and the risk of HCC using a meta-analysis of the published studies. Published literature from PubMed and Embase databases was systematically searched to identify relevant studies before October 2014. The Begg test was used to measure publication bias. Sensitivity analyses were performed to ensure the authenticity of the outcome. The meta-analysis results showed significant association between the MTHFR A1298C polymorphism and HCC risk (CC vs AA: OR = 0.52, 95%CI = 0.33-0.81; CC vs AC: OR = 0.50, 95%CI = 0.32-0.79; dominant model: OR = 1.94, 95%CI = 1.24-3.02; recessive model: OR = 1.00, 95%CI = 0.84-1.18). In the subgroup analysis, significant associations between the MTHFR A1298C polymorphism and HCC risk were found in Asians (CC vs AA: OR = 0.46, 95%CI = 0.27-0.78; CC vs AC: OR = 0.41, 95%CI = 0.24-0.71; dominant model: OR = 2.27, 95%CI = 1.33-3.86; recessive model: OR = 1.03, 95%CI = 0.86-1.24). Our results suggest that the MTHFR A1298C polymorphism might be related to increased risk of HCC in Asians. Further large and well-designed studies are needed to confirm these conclusions.

Fas -670A/G (rs1800682) polymorphism and digestive cancer risk in Asians: a meta-analysis.

Tumorigenesis is a multistep process that begins with the abrogation of normal controls of apoptosis and cell proliferation, and the Fas receptor-ligand system is a key regulator of apoptosis. The Fas -670 A/G single-nucleotide polymorphism (SNP) has been demonstrated to affect the expression of the Fas gene by altering the transcriptional activity in this gene's promoter. However, the association between the Fas -670 A/G polymorphism and digestive cancer risk is still controversial and ambiguous in the Asian population, so we conducted a meta-analysis to confirm and clarify the association between the Fas -670 A/G polymorphism and digestive cancer. A search of PubMed, China National Knowledge Infrastructure (CNKI), and WanFang databases was conducted and encompassed all available articles that had been published up to July 20, 2013. Overall, 15 case-control studies containing 3692 cases and 4895 controls were retrieved based on search criteria for digestive cancer susceptibility related to -670A/G SNP. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. In the overall analysis, the country type and source of control subgroups, no association between the Fas -670 A/G polymorphism and digestive cancer risk was found. However, in the digestive cancer-type subgroups, a significant protective effect was detected between Fas -670 A/G polymorphism and hepatocellular carcinoma in Asians (AG vs. GG: OR=0.89, 95% CI=0.80-0.99; AA+AG vs. GG: OR=0.93, 95% CI=0.87-1.00). Our investigations demonstrated that the Fas -670 A/G polymorphism might decrease the hepatocellular carcinoma risk in Asian populations. Further studies based on larger sample sizes, other ethnicities, and gene-environment interactions should be conducted to further understand the role of Fas -670 A/G polymorphism in digestive cancer risk.

Differences in clinical characteristics and treatment in hepatocellular carcinoma between Asians and non-Asians.

289 Background: Studies have demonstrated clinical differences in hepatocellular carcinoma (HCC) between Asians (AS) and non-Asians (NAS). In the US, AS are less likely to undergo liver transplant compared to Caucasians. Despite the large immigrant population in Canada, there has been no prior comparison of HCC in AS and NAS in the context of the Canadian universal health care system. We retrospectively evaluated the ethnic differences in HCC at the largest cancer centre in Canada. Methods: We analyzed 268 patients who enrolled in a Genetic Epidemiology Study of HCC (April 2010 to February 2013), where patients were asked to complete a questionnaire and give a blood sample at their first visit. Relevant clinical data were extracted and analyzed by descriptive statistics, t-test or Chi-square test. Results: The study population had a mean age of 61 years and 83% males. There were 45% AS, 49% Caucasians, and 6% other ethnicities. Etiologies of HCC included: Hepatitis B (HBV) 34%, Hepatitis C (HCV) 32%, non-alcoholic steatohepatitis 15%, alcohol 18%. Compared to NAS, HCC patients of Asian ancestry had significantly higher rates of HBV (60% vs. 12%, p&lt;0.001). At diagnosis, 83% of patients were Child-Pugh A (mean MELD score 9.2). Ethnicity had no impact on Child-Pugh class, multifocal disease or macrovascular invasion. However, MELD scores were lower in AS (p=0.02). Overall, 71% of cases were initially treated with curative intent. Patients underwent various treatment modalities: liver transplant 13%, resection 31%, radiofrequency ablation 39%, transarterial chemoembolization (TACE) 21%, radiation 17%, systemic therapy 27%. AS had higher resection rates (41% vs. 22%, p&lt;0.001), while no differences were observed for other treatments. Duration of response was 11.7 months for TACE (AS 14.2, NAS 10.5), 7.5 months for sorafenib (AS 6.8, NAS 8.1). Rate of intolerance to sorafenib was 24% (AS 27%, NAS 22%, p=0.63). This analysis was limited by inherent bias in the selection of study patients. Conclusions: AS with HCC tend to have HBV and lower MELD scores, and to undergo resection in a public health care setting with no differences in the uptake of other therapies. An analysis of survival based on ethnicity will be reported.

Clinical Presentation and Survival of Asian and Non-Asian Patients with HCV-Related Hepatocellular Carcinoma

Hepatitis C virus (HCV) is an important cause of hepatocellular carcinoma (HCC) in Asians; however, it is often overlooked due to the high prevalence of hepatitis B virus in Asians. This study examines HCV-related HCC in Asians. We conducted a retrospective cohort study of 792 consecutive Asian (n = 220) and non-Asian (n = 572) patients with HCV-related HCC identified at Stanford University Medical Center using International Classification of Diseases-9 diagnosis between July 1996 and June 2012. Asian patients were much older [66 (38-88) vs. 56 (31-87) years, P < 0.0001] and more likely to be female (33 vs. 19 %, P < 0.0001). A larger proportion of Asians were diagnosed with HCC within 2 years of HCV diagnosis (35 vs. 20 %, P = 0.001). Asian patients were more likely to undergo palliative therapy (46 vs. 28 %) and less likely to be listed for liver transplantation (20 vs. 48 %, P < 0.001), despite similar rates of meeting Milan criteria (52 vs. 58 %, P = 0.16). Overall, there was a trend for higher median survival rates in Asians (30 vs. 21 months, P = 0.091). Asians had higher long-term survival with palliative therapy only (5-year survival: 28 vs. 10 %, P < 0.0001); however, survival was similar among patients listed for liver transplantation. There were distinct differences in clinical presentations of Asian and non-Asian patients with HCV-related HCC. Asians with HCV-related HCC are less likely to undergo liver transplantation and more likely to have delayed HCV diagnosis. Improved strategies in HCV screening in Asians are needed, as it may lead to earlier diagnosis and treatment of HCV infection and possible prevention of HCC development.

Significant association between MTHFR C677T polymorphism and hepatocellular carcinoma risk: a meta-analysis

Previous studies investigated the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and hepatocellular carcinoma risk, but the impact of MTHFR C677T polymorphism on hepatocellular carcinoma was still unclear, owing to the obvious inconsistence from those studies. This study aimed to quantify the strength of the association between MTHFR C677T polymorphism and hepatocellular carcinoma risk by performing a meta-analysis. We searched the PubMed and Wanfang databases for studies on the association between MTHFR C677T polymorphism and hepatocellular carcinoma risk. We estimated the pooled odds ratios (ORs) with their 95% confidence intervals (95% CIs) to assess the association. Fifteen studies with 8,625 participants were finally included into the meta-analysis. Meta-analyses of total 15 studies suggested that MTHFR C677T polymorphism was significantly associated with an increased risk of hepatocellular carcinoma under two main genetic models (for TT versus CC, OR = 1.19, 95% CI 1.03-1.37, P = 0.016; for TT versus CT/CC, OR = 1.14, 95% CI 1.01-1.28, P = 0.032). Subgroup meta-analyses suggested that MTHFR C677T polymorphism was associated with an increased risk of hepatocellular carcinoma in Asians, but not in Caucasians. Thus, individuals with homozygote genotype TT of MTHFR C677T have obviously increased risk of hepatocellular carcinoma.

GSTT1 null genotype contributes to hepatocellular carcinoma risk: a meta-analysis

Studies investigating the association between genetic polymorphism of glutathione S-transferase T1 (GSTT1) and hepatocellular carcinoma (HCC) risk have reported conflicting results. Therefore, we conducted this meta-analysis to provide more precise evidence. Databases including PubMed, Embase, SCOPUS, ISI Web of Science, and Wangfang were searched for relevant studies. Potential sources of heterogeneity were also assessed by subgroup analysis. Funnel plots and Egger's linear regression were used to test publication bias among the articles. Finally, a total of 28 studies involving 3,897 HCC patients and 6,117 controls were included in this meta-analysis. In a combined analysis, the summary odds ratio for HCC of the GSTT1 null genotype was 1.43 (95% confidence interval (CI) 1.22–1.68, P < 10(−5)). In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians for GSTT1 null polymorphism, while no significant associations were found among Caucasian, South Asian, and African populations. When stratified by a source of controls, both population- and hospital-based studies get consistent positive results. By pooling data from 10 studies (1,639 cases and 2,224 controls) that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for HCC (odd ratio = 1.85, 95% CI 1.37–2.49) was detected for individuals with combined deletion mutations in both genes compared with positive genotypes. No evidence of publication bias was observed. Our result suggests that the GSTT1 null genotype contributes to an increased risk of HCC in East Asians and that interaction between unfavorable GSTs genotypes may exist.

Human genetic variation and the risk of hepatocellular carcinoma development.

Our understanding of the patho-physiology of hepatocellular carcinoma (HCC) is still much fragmented making difficult the improvement of the clinical outcome for the majority of HCC patients. Discovery of single nucleotide polymorphisms (SNPs) associated with individual susceptibility to HCC may enable the persons at risk to adapt their lifestyle and legitimate implementation by their doctors of surveillance programs facilitating early detection and subsequent management of the disease. To shed light on the influence of human genetic variation on HCC, we conducted a review of the meta-analyses of candidate SNPs and genome wide association studies (GWAS) performed for HCC by search of PubMed and Google Scholar databases. Genetic variations occurring in pathways historically considered as instrumental for liver tumorigenesis (TP53/MDM2, HLA, glutathione-S-transferases/cytochrome P540, TNFα/TGFβ, etc…) are discussed. An immense majority of the data has been produced in Eastern Asia (China, Japan, Korea). These meta-analyses indicate that the TP53, the MDM2 SNP309 G and the GSTT1 null genotype contribute to an increased risk of HCC both in Asians and Caucasians. Significant differences of odds ratios are, however, commonly observed between Eastern-Asians and other populations. Amazingly, GWAS studies performed so far exclusively with HCC patients from Eastern Asia produced drastically different outcomes pointing at unrelated biological pathways. The small magnitude of the risk associated with the genetic variants raises the question of their future utility as markers in clinical practice. An assessment of their impact on tumor progression (vascular invasion, metastases) remains, however, to be done and may prove to be more useful for clinicians. Finally, the evaluation of these variants is not available for various populations of the world and particularly for Subsaharan Africans who are especially affected by HCC.