Aldehyde dehydrogenase expression may be a prognostic biomarker and associated with liver cirrhosis in patients resected for hepatocellular carcinoma

Background: Several members of the aldehyde dehydrogenase (ALDH) isoenzyme family have been suggested as prognostic biomarkers in patients with hepatocellular carcinoma (HCC). The aim of the study was to evaluate overall ALDH family member expression by RNA sequencing and hierarchical clustering in tumor and adjacent liver tissue to predict survival and evaluate correlation with liver cirrhosis in patients undergoing liver resection for HCC. Methods: We included patients having undergone liver resection for HCC between May 2014 and January 2018 at a tertiary referral university hospital (Copenhagen University Hospital, Rigshospitalet, Denmark). ALDH family member expression was evaluated by RNA sequencing of tumor and non-tumor liver tissue. Hierarchical clus-tering of ALDH genes was used to identify patient groups and correlations were established with overall survival, recurrence and histological features. Results: Fifty-two patients were included with 88.5% males, 84.6% with only one HCC and 73.1% with a non-cirrhotic background liver. Median follow-up was 45.7 months. Patients in one cluster defined by its ALDH expression in the tumor tissue showed significantly worse overall survival (log-rank p = 0.015), also when adjusted for age, cirrhosis, microvascular invasion, resection margins and tumor number (hazard ratio 4.2, 95% confidence interval (CI) 1.5-11.9, p = 0.007). When evaluated individually, the isoenzyme ALDH1L1 may be of particular importance. Several clusters in non-tumor tissue were correlated with cirrhosis. Especially one cluster had a high discriminative ability (area under receiver operating characteristic curve of 0.839) and remained significantly associated with cirrhosis when corrected for age, microvascular invasion, resection margins and tumor number (odds ratio 44.2, 95% CI 5.5-352.0, p < 0.001). The combination of ALDH and a previously identified candidate biomarker (expression signature of the transcriptional targets of the peroxisome proliferator-activated receptors (PPARs)) may add additional prognostic value. Conclusion: The expression of ALDH family members in HCC was correlated with overall survival. Moreover, ALDH expression in non-tumor liver tissue was correlated with cirrhosis. Members of the ALDH family of en-zymes may serve as a prognostic biomarker as well as potential targets for systemic treatment.

Automated summary

In this study, the expression of ALDH family members in tumor and adjacent liver tissue of HCC patients was evaluated. The results showed that the expression of ALDH family members was correlated with overall survival and liver cirrhosis. Especially, ALDH1L1 may play a significant role. These findings suggest that ALDH family members may serve as prognostic biomarkers and potential targets for systemic treatment in HCC.