A Differentiation-Related Gene Prognostic Index Contributes to Prognosis and Immunotherapy Evaluation in Patients with Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most common gastrointestinal tumor with a poor prognosis, which is associated with poor differentiation of tumor cells. However, the potential value of cell differentiation-related molecules in predicting the benefit and prognosis of immune checkpoint inhibitors (ICI) therapy remains unknown. Herein, to investigate the differentiation trajectory of HCC cells and their clinical significance, a differentiation-related gene prognostic index (DRGPI) based on HCC differentiation-related genes (HDRGs) was constructed to elucidate the immune characteristics and therapeutic benefits of ICI in the HCC subgroup defined by DRGPI. Single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from four HCC samples were integrated for bioinformatics analysis. Then, PON1, ADH4, SQSTM1, HSP90AA1, and STMN1 were screened out to construct a DRGPI. More intriguingly, RT-qPCR validation of the expression of these genes yielded consistent results with the TCGA database. Next, the risk scoring (RS) constructed based on DRGPI suggested that the overall survival (OS) of the DRGPI-high patients was significantly worse than that of the DRGPI-low patients. A nomogram was constructed based on DRGPI-RS and clinical characteristics, which showed strong predictive performance and high accuracy. The comprehensive results indicated that a low DRGPI score was associated with low TP53 mutation rates, high CD8 T cell infiltration, and more benefit from ICI therapy. Homoplastically, the high DRGPI score reflected the opposite results. Taken together, our study highlights the significance of HCC cell differentiation in predicting prognosis, indicating immune characteristics, and understanding the therapeutic benefits of ICI, and suggests that DRGPI is a valuable prognostic biomarker for HCC.

Identification and validation of a novel predictive signature based on hepatocyte-specific genes in hepatocellular carcinoma by integrated analysis of single-cell and bulk RNA sequencing

“…Our analysis of somatic mutation frequencies revealed TP53 mutation as the most prominent difference between high- and low-risk groups. Our findings align with existing research showing that TP53 mutation, the most prevalent mutation in cancer, is associated with increased tumor aggressiveness and poorer prognosis, particularly in HCC patients [ 45 ]. Compared to existing studies on HCC prognostic models utilizing bulk RNA-seq technology, such as those based on pyroptosis-related gene models [ 46 ] and immune infiltration-related gene models [ 47 ], there is a notable gap in research at the single-cell level.…”

Identification of cell differentiation trajectory-related gene signature to reveal the prognostic significance and immune landscape in prostate cancer based on multiomics analysis

“…Utilizing scRNA-seq data from PCa patients, our study delved into marker genes that contribute to gene heterogeneity in the TME through cell differentiation trajectories. Numerous effective clinical prediction models have been established in previous research, offering the potential for enhanced early diagnosis and prognosis for cancer patients [ 31 , [52] , [53] , [54] ]. Employing WGCNA, we identified six crucial marker genes influencing recurrence-free survival in PCa patients.…”

Role of peritumoral tissue analysis in predicting characteristics of hepatocellular carcinoma using ultrasound-based radiomics

“…Accurate prediction of this indicator contributes to an understanding of the differentiation status of liver cancer cells, thus providing robust support for the design of treatment strategies. Compared with highly differentiated tumors, poorly differentiated tumors typically exhibit faster growth rates and relatively poorer treatment responses 23 . The cytokeratin CK7 is an important immunohistochemical marker in liver cancer research.…”