Genetic biomarkers for hepatocellular cancer risk in a caucasian population

AIMTo uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma (HCC) susceptibility in Caucasians.METHODSThe present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two, independent, HCC-free, age/sex-matched control groups. The HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver transplantation. The first control group comprised 167 patients that were matched to the HCC cohort for the percentage of hepatitis B (HBV) and/or hepatitis C (HCV) infections. A second control group included 192 virus-free, healthy individuals that were used to evaluate the generalizability of the identified predictive markers. All cases and controls were Caucasian. The three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related pathways. The study end-point was to assess the association between genetic variants and HCC onset.RESULTSFive genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/HCV. According to a dominant model, reduced HCC risk was associated with three polymorphisms: ERCC1 rs3212986 (OR = 0.46, 95% CI: 0.30-0.71, P = 0.0005), GST-P1 rs1138272 (OR = 0.41, 95% CI: 0.21-0.81, P = 0.0097), and CYP17A1 rs743572 (OR = 0.50, 95% CI: 0.31-0.79, P = 0.0032). Conversely, according to a recessive model, increased HCC risk was associated with two polymorphisms: XRCC3 rs1799794 (OR = 3.70, 95% CI: 1.02-13.39, P = 0.0461) and ABCB1 rs1128503 (OR = 2.06, 95% CI: 1.18-3.61, P = 0.0111). These associations remained significant in a subgroup analysis, where patients were stratified according to viral status (HBV-or HCV-positive serology). Two variants exhibited a serology-specific effect: ABCB1 rs1128503 (OR = 4.18, 95% CI: 1.55-11.29, P = 0.0048) showed an effect in the HBV-positive subgroup; and ERCC1 rs3212986 (OR = 0.33, 95% CI: 0.18-0.60, P = 0.0003) showed an effect in the HCV-positive subgroup. Among the five markers identified, ERCC1 rs3212986 (OR = 0.43, P < 0.0001) and CYP17A1 rs743572 (OR = 0.73, P = 0.0310) had a different distribution in patients with HCC compared to healthy individuals. With a recursive partitioning approach, we also demonstrated that significant gene-gene interactions between ERCC1 rs3212986, CYP17A1 rs743572, GST-P1 rs1138272, and the previously described UGT1A7*3 predictive marker, played a role in the complex trait of HCC susceptibility.CONCLUSIONWe identified five polymorphisms and interactions that contributed crucially to predicting HCC risk. These findings represented an important step towards improving HCC diagnosis and management

Genetic biomarkers for hepatocellular cancer risk in a caucasian population

AIMTo uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma (HCC) susceptibility in Caucasians.METHODSThe present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two, independent, HCC-free, age/sex-matched control groups. The HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver transplantation. The first control group comprised 167 patients that were matched to the HCC cohort for the percentage of hepatitis B (HBV) and/or hepatitis C (HCV) infections. A second control group included 192 virus-free, healthy individuals that were used to evaluate the generalizability of the identified predictive markers. All cases and controls were Caucasian. The three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related pathways. The study end-point was to assess the association between genetic variants and HCC onset.RESULTSFive genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/HCV. According to a dominant model, reduced HCC risk was associated with three polymorphisms: ERCC1 rs3212986 (OR = 0.46, 95% CI: 0.30-0.71, P = 0.0005), GST-P1 rs1138272 (OR = 0.41, 95% CI: 0.21-0.81, P = 0.0097), and CYP17A1 rs743572 (OR = 0.50, 95% CI: 0.31-0.79, P = 0.0032). Conversely, according to a recessive model, increased HCC risk was associated with two polymorphisms: XRCC3 rs1799794 (OR = 3.70, 95% CI: 1.02-13.39, P = 0.0461) and ABCB1 rs1128503 (OR = 2.06, 95% CI: 1.18-3.61, P = 0.0111). These associations remained significant in a subgroup analysis, where patients were stratified according to viral status (HBV-or HCV-positive serology). Two variants exhibited a serology-specific effect: ABCB1 rs1128503 (OR = 4.18, 95% CI: 1.55-11.29, P = 0.0048) showed an effect in the HBV-positive subgroup; and ERCC1 rs3212986 (OR = 0.33, 95% CI: 0.18-0.60, P = 0.0003) showed an effect in the HCV-positive subgroup. Among the five markers identified, ERCC1 rs3212986 (OR = 0.43, P < 0.0001) and CYP17A1 rs743572 (OR = 0.73, P = 0.0310) had a different distribution in patients with HCC compared to healthy individuals. With a recursive partitioning approach, we also demonstrated that significant gene-gene interactions between ERCC1 rs3212986, CYP17A1 rs743572, GST-P1 rs1138272, and the previously described UGT1A7*3 predictive marker, played a role in the complex trait of HCC susceptibility.CONCLUSIONWe identified five polymorphisms and interactions that contributed crucially to predicting HCC risk. These findings represented an important step towards improving HCC diagnosis and management

Rational Enzyme Design Without Structural Knowledge: A Sequence-Based Approach for Efficient Generation of Glycosylation Catalysts

We present an enzyme engineering approach based solely on amino-acids sequence to convert glycoside hydrolases into transglycosylases. We demonstrate its effectiveness on enzymes form five different glycoside hydrolase families, synthesizing various oligosaccharides containing different α-/β-pyranosides or furanosides in one-step with high yields.</p

A cholestatic pattern predicts major liver-related outcomes in patients with non-alcoholic fatty liver disease

Background &amp; aims: NAFLD patients usually have an increase in AST/ALT levels, but cholestasis can also be observed. We aimed to assess in subjects with NAFLD the impact of the (cholestatic) C pattern on the likelihood of developing major liver-related outcomes (MALO). Methods: Five hundred and eighty-two consecutive patients with biopsy-proven NAFLD or a clinical diagnosis of NAFLD-related compensated cirrhosis were classified as hepatocellular (H), C and mixed (M) patterns, by using the formula (ALT/ALT Upper Limit of Normal-ULN)/(ALP/ALP ULN). MALO were recorded during follow-up. An external cohort of 1281 biopsy-proven NAFLD patients was enrolled as validation set. Results: H, M and C patterns were found in 153 (26.3%), 272 (46.7%) and 157 (27%) patients respectively. During a median follow-up of 78 months, only 1 (0.6%) patient with H pattern experienced MALO, whilst 15 (5.5%) and 38 (24.2%) patients in M and C groups had MALO. At multivariate Cox regression analysis, age &gt;55 years (HR 2.55, 95% CI 1.17-5.54; p = .01), platelets &lt;150 000/mmc (HR 0.14, 95% CI 0.06-0.32; p &lt; .001), albumin &lt;4 g/L(HR 0.62, 95% CI 0.35-1.08; p = .09), C versus M pattern (HR 7.86, 95% CI 1.03-60.1; p = .04), C versus H pattern(HR 12.1, 95% CI 1.61-90.9; p = .01) and fibrosis F3-F4(HR 35.8, 95% CI 4.65-275.2; p &lt; .001) were independent risk factors for MALO occurrence. C versus M pattern(HR 14.3, 95% CI 1.90-105.6; p = .008) and C versus H pattern (HR 15.6, 95% CI 2.10-115.1; p = .0068) were confirmed independently associated with MALO occurrence in the validation set. The immunohistochemical analysis found a significantly higher prevalence of moderate-high-grade ductular metaplasia combined with low-grade ductular proliferation in C pattern when compared with the biochemical H pattern. Gene expression analysis showed a lower expression of NR1H3, RXRα and VCAM1 in patients with the C pattern. Conclusions: The presence of a cholestatic pattern in patients with NAFLD predicts a higher risk of MALO independently from other features of liver disease