UGT1A polymorphisms as genetic biomarkers for hepatocellular carcinoma risk in Caucasian population

Mattia, Elena De; Cecchin, Erika; Polesel, Jerry; Lupo, Francesco; Tiribelli, Claudio; Crovatto, M; Buonadonna, Angela; Toffoli, Giuseppe

doi:10.1111/liv.13411

Cited by 21 publications

(14 citation statements)

References 48 publications

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“…The ethnicity of the population being studied is a crucial factor in case-control studies, because polymorphism frequency varies greatly with geographical origin. This association could give rise to ethnicity-specific phenotypic effects[ 4 , 14 ]. The present study revealed some novel genetic markers that could be used as early diagnosis indicators for liver cancer susceptibility in Caucasians.…”

Section: Discussionmentioning

confidence: 99%

“…The CART analysis generated a distinctive clustering of subjects, according to different probabilities of developing liver cancer. These data pointed out that previously acknowledged predictive markers, such as the UGT1A*3 polymorphism[ 14 ], should be considered in association with novel identified genetic variants for properly defining the complex trait of HCC susceptibility. In particular, ERCC1 rs3212986 was shown to be the most relevant polymorphism for HCC risk stratification, because it appeared twice in the generated tree.…”

Section: Discussionmentioning

confidence: 99%

“…Recursive partitioning was performed to elucidate high-order relationships among genetic factors, when stratifying patients between HCC cases and HBV/HCV group. The analysis was carried out with the five genetic variants that were identified in the present study as significant predictors of HCC risk and with the previously described UGT1A markers ( i.e., UGT1A1 *28, UGT1A9 *22, UGT1A7 *3)[ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported that the low-activity alleles, UGT1A1 *28, UGT1A7 *3, UGT1A9 *22, and related haplotypes may play a protective role against HCC development in Caucasian populations. These alleles positively modulate the serum levels of beneficial molecules, like bilirubin[ 14 ]. The present study aimed to extend genetic analyses by identifying additional molecular markers that could be integrated into the HCC risk stratification algorithms used in liver cancer prevention strategies.…”

Section: Introductionmentioning

confidence: 99%

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Genetic biomarkers for hepatocellular cancer risk in a caucasian population

Mattia

Cecchin

Polesel

et al. 2017

WJG

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic biomarkers for hepatocellular cancer risk in a caucasian population

Mattia

Cecchin

Polesel

et al. 2017

WJG

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“…The last episode in the search for the dangerous liaisons between UGT1A and HCC has been published recently in Liver International. 15 In this work, de Mattia and coworkers conducted a case-control study on patients transplanted for HCC (cases, n=192), and on two sets of controls, the first set composed of patients chronically infected with hepatitis B or C viruses and the second set composed of healthy blood donors. The authors looked for the presence of six polymorphisms located in UGT1A1 (n=3), UGT1A7 (n=2) and UGT1A9 (n=1).…”

Section: Editorialmentioning

confidence: 99%