Published online Sep 28, 2017. doi: 10.3748/wjg.v23.i36.6674
Peer-review started: February 28, 2017
First decision: April 28, 2017
Revised: May 17, 2017
Accepted: July 4, 2017
Article in press: July 4, 2017
Published online: September 28, 2017
To uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma (HCC) susceptibility in Caucasians.
The 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.
Five 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.
We identified five polymorphisms and interactions that contributed crucially to predicting HCC risk. These findings represented an important step towards improving HCC diagnosis and management.
Core tip: It is a great challenge to define new biomarkers of hepatocellular carcinoma (HCC) risk for HCC management. This work identified five genetic markers in key pathways linked to hepatocarcinogenesis (ERCC1 rs3212986, GSTP1 rs1138272, CYP17A1 rs743572, XRCC3 rs1799794, and ABCB1 rs112850), which could predict individual HCC susceptibility, particularly in a high-risk [hepatitis B viral/hepatitis C viral (HCV)-infected] Caucasian population. We also identified potential gene-gene interactions that should be included in the definition of HCC risk. These findings could contribute to improved HCC surveillance, early cancer diagnoses, and potential curative therapies. For patients with HCV, these markers could be considered selection criteria for the personalized use of recently developed, highly expensive anti-viral therapies.