Integrated analysis of the impact of age on genetic and clinical aspects of hepatocellular carcinoma

Abstract

Despite the rapid growing and aging of populations worldwide, our knowledge on hepatocellular carcinoma (HCC) is still age-standardized rather than age-specific, with only few studies exploring the topic from a genetic point of view. Here, we analyze clinical and genetic aspects of HCC in patients of different age groups with the major attention directed to children (≤20 y) and elderly groups (≥80 y). A number of significant differences were found in elderly patients compared to children group, including smaller tumor size (P=0.001) and improved survival rates (P=0.002). Differences in gene mutations, copy number variants, and mRNA expressions were identified between the groups, with alteration rates for some genes like AKR1B10 increasing significantly with the age of patients. Immunohistochemistry testing of AKR1B10 showed a significant difference in expression levels at the age of 40 (30.77% high expression rate in patients younger than 40 compared to 51.57% in older patients) (P=0.043). Expression levels also differed between HCC tissues (49.64%) and near-tumor tissues (6.58%) (P<0.001). These findings contribute to the limited data available regarding the age-specific aspects of HCC patients, and support the need to address potential differences in the diagnosis, treatment, and prevention strategies of HCC.

Keywords: AKR1B10; Copy Number Variants; Hepatocellular Carcinoma; aging; gene mutation; m RNA expression.

Figure 1

The survival curves for children and elderly groups of patients in the clinical analysis.

Figure 2

The 25 commonly over-expressed genes in HCC patients and the heat-map of their expression patterns in TCGA liver cancer patients, along with patients liver cancer type and age of diagnosis.

Figure 3

The survival curves of TCGA liver cancer patients with and without alterations in mRNA expression patterns of the selected 25 genes.

Figure 4

(A, B) The overall survival (OS) and disease free survival (DFS) curves in patients with and without mRNA over-expression in AKR1B10. (C) The correlation between AKR1B10 mRNA expression level in liver cancer and patient survival from the pathology atlas of the human cancer transcriptome .Corresponding expression cutoff= 26.8 FPKM. 5-year survival for patients with high expression= 41% , 5-year survival for patients with low expression= 57%, and log-rank P value = 0.00216. URL: https://www.proteinatlas.org/ENSG00000198074-AKR1B10/pathology/tissue/liver+cancer#ihc.

Figure 5

Representative images of AKR1B10 immunohistochemistry staining in tissues. (A-B) represent negative staining (score: 0). (C-D) (score: 1), (E-F) (score: 2), (G-H) (score: 4) all represent weak staining. (I-J) (score: 6) and (K-L) (score: 8) represent strong staining. Scores 0 to 4 are categorized as low expression of AKR1B10, while scores 6 to 8 are considered as high expression.

Figure 6

(A) AKR1B10 IHC expression differences between HCC and Near-tumor tissues. (P<0.001), (B) AKR1B10 IHC expression differences at the age of 40. (P=0.043).

Figure 7

Genes involved in G2 cell cycle arrest pathway regulated by TP53.