ALDH1L1 variant rs2276724 and mRNA expression predict post-operative clinical outcomes and are associated with TP53 expression in HBV-related hepatocellular carcinoma

Abstract

Aldehyde dehydrogenase 1 family member L1 (ALDH1L1) is downregulated in hepatocellular carcinoma (HCC) tumors, and its decreased expression is associated with the poor prognosis of HCC patients. We, therefore, evaluated the effect of single nucleotide polymorphisms (SNPs) of ALDH1L1, and its mRNA expression on the survival of hepatitis B virus (HBV)‑related HCC patients and the association with tumor protein p53 (TP53) expression. ALDH1L1 SNPs in 415 HBV-related HCC patients were genotyped via direct sequencing. Expression profile chip datasets and survival information were obtained from GSE14520. The C allele (CT/CC) carriers of rs2276724 were significantly associated with a favorable prognosis [adjusted P=0.040; adjusted hazard ratio (HR)=0.725; 95% confidence interval (CI)=0.533-0.986]. Joint-effect analyses suggested that the CT/CC genotype of rs2276724 in TP53-negative patients was significantly associated with a decreased risk of death, compared to the TT genotype of rs2276724 in TP53-positive patients (adjusted P=0.037; adjusted HR=0.621; 95% CI=0.396-0.973). Furthermore, low expression of ALDH1L1 predicted a poor prognosis for the HBV-related HCC patients (adjusted P=0.04 for disease-free survival; adjusted P=0.001 for overall survival). Patients with high ALDH1L1 expression and low TP53 expression were significantly associated with a decreased risk of recurrence and death, and patients with a high TP53 expression were also significantly associated with a decreased risk of death in HBV-related HCC, compared with low ALDH1L1 and low TP53 expression. Our results suggest that ALDH1L1 may be a biomarker for predicting postoperative clinical outcomes. Moreover, ALDH1L1-rs2276724 and mRNA expression were associated with TP53 expression in HBV-related HCC patients.

Figure 1.

(A) ALDH1L1 gene expression in multiple normal tissues. (B) Comparison of ALDH1L1 expression between HCC and normal tissues by MERAV. (C) Comparison of ALDH1L1 expression between HCC and non-tumor tissues by GSE14520. ALDH1L1, aldehyde dehydrogenase 1 family member L1; HCC, hepatocellular carcinoma.

Figure 2.

Stratified analyses of associations of rs2276724 with the OS in the patients with HBV-related HCC. All variables were stratified by favorable and adverse strata. HBV, hepatitis B virus; HCC, hepatocellular carcinoma; OS, overall survival.

Figure 3.

Survival curves of patients with rs2276724 and joint-effect analyses with different levels of TP53 expression. (A) Kaplan-Meier survival curves for patients with TT, CT, and CC genotypes. (B) Kaplan-Meier survival curves for patients with TT and CT/CC genotypes. (C) Kaplan-Meier survival curves for patients with different levels of TP53 expression. (D) Kaplan-Meier survival curves for joint-effect analyses of patients with different rs2276724 genotypes and different levels of TP53 expression. TP53, tumor protein p53.

Figure 4.

(A) Correlations between ALDH1L1 and TP53 mRNA expression using GSE14520. (B) A gene interaction diagram of the ALDH1L1 and TP53 genes using GeneMANIA. ALDH1L1, aldehyde dehydrogenase 1 family member L1; TP53, tumor protein p53.

Figure 5.

Stratified analyses of the associations of different ALDH1L1 mRNA expression levels with the GSE14520 prognosis of HCC patients. All variables were stratified by favorable and adverse strata. (A) Stratified analysis between ALDH1L1 and DFS. (B) Stratified analysis between ALDH1L1 and the OS. ALDH1L1, aldehyde dehydrogenase 1 family member L1; HCC, hepatocellular carcinoma; DFS, disease-free survival; OS, overall survival.

Figure 6.

Survival curves for the GSE14520 analyses of HCC patients with different ALDH1L1 mRNA expression levels, and the joint-effect analyses with TP53 mRNA expression levels. (A) Kaplan-Meier survival curves for DFS for different ALDH1L1 expression levels. (B) Kaplan-Meier survival curves for the OS analyses of different ALDH1L1 expression levels. (C) Kaplan-Meier survival curves for the joint-effect analyses for different ALDH1L1 and TP53 mRNA expression levels; analysis for DFS. (D) Kaplan-Meier survival curves for the joint-effect analyses for different ALDH1L1 and TP53 mRNA expression levels; analysis for OS. HCC, hepatocellular carcinoma; TP53, tumor protein p53; ALDH1L1, aldehyde dehydrogenase 1 family member L1; DFS, disease-free survival; OS, overall survival.