Identification of chromosomal instability-associated genes as hepatocellular carcinoma progression-related biomarkers to guide clinical diagnosis, prognosis and therapy.

ABSTRACT

Hepatocellular carcinoma (HCC) is a type of cancer characterized by high heterogeneity and a complex multistep progression process. Significantly-altered biomarkers for HCC need to be identified. Differentially expressed genes and weighted gene co-expression network analyses were used to identify progression-related biomarkers. LASSO-Cox regression and random forest algorithms were used to construct the progression-related prognosis (PRP) score. Three chromosomal instability-associated genes (KIF20A, TOP2A, and TTK) have been identified as progression-related biomarkers. The robustness of the PRP scores were validated using four independent cohorts. Immune status was observed using the single-sample gene set enrichment analysis (ssGSEA). Comprehensive analysis showed that the patients with high PRP score had wider genomic alterations, more malignant phenotypes, and were in a state of immunosuppression. The diagnostic models constructed via logistic regression based on the three genes showed satisfactory performances in distinguishing HCC from cirrhotic tissues or dysplastic nodules. The nomogram combining PRP scores with clinical factors had a better performance in predicting prognosis than the tumor node metastasis classification (TNM) system. We further confirmed that KIF20A, TOP2A, and TTK were highly expressed in HCC tissues than in cirrhotic tissues. Downregulation of all three genes aggravated chromosomal instabilities in HCC and suppressed HCC cells viability both in vitro and in vivo. Overall, our study highlights the important roles of chromosomal instability-associated genes during the progression of HCC and their potential clinical diagnosis and prognostic value and provides promising new ideas for developing therapeutic strategies to improve the outcomes of HCC patients.