Genetic Expression and Mutation Profile Analysis in Different Pathologic Stages of Hepatocellular Carcinoma Patients

Abstract

Background: The expression and mutation of multiple genes are involved in the complicated mechanism regarding the occurrence and development of hepatocellular carcinoma (HCC). The clinical pathological stage of HCC is closely linked to clinical prognosis of liver cancer. Methods: This study aims at analyzing the gene expression and mutation profile of different clinical pathological stages of HCC (stage I, II, III-IV), based on 367 HCC cases included in TCGA cohort. Findings: We identified a series of targeting genes with copy number variation (CNV), which is statistically associated with gene expression. For instance, compared with the normal group, CCNE 2 gene is highly expressed in the tumor group and specific stage I group, which are associated with three CNV types of single deletion, single gain, and amplification mutations. Protein interaction network construction and followed Molecular Complex Detection analysis indicated that the high expression of some cell cycle-related genes in HCC, such as TTK, CDC20, ASPM, is positively correlated with CNV. Non-synonymous mutations mainly existed in some genes, such as TTN, TP53, CTNNB1, MUC16, and ALB, however, we did not observe the association between the gene mutation frequency and the clinical pathological grade distribution. The rs121913396 and rs121913400 polymorphisms within the CTNNB1 gene were associated with the high expression of CTNNB1 protein, but not linked to the clinical prognosis of HCC. We performed the random forest and decision tree approaches for the modeling analysis and identified a group of genes related to different HCC pathological grades, such as the lowly expressed VIPR1, FAM99A, and GNA14 genes, or highly expressed CEP55, SEMA3F, and PRR11. Moreover, we conducted a principal component analysis (PCA) to obtain several genes associated with different pathological grades, including SLC27A5, ADAM17, SNRPA, SNRPD2, and ALDH2. Finally, we confirmed the highly expressed GAS2L3, SNRPA, SNRPD2 genes in the HCC tissues, for the first time, through a Chinese HLivH060PG02 cohort analysis. Interpretation: The identification of the targeting genes, including GAS2L3, SNRPA, SNRPD2, provides insight into the molecular mechanisms associated with different prognosis of HCC. Funding Statement: This work was supported by grants from the Innovation Team Development Plan of the Ministry of Education (IRT13085 to JY), National Nature Science Foundation of China (31670759 to JY, 31571380 to XG, 81572882 to ZY, 31701182 to CS), Excellent Talent Project of Tianjin Medical University (to JY), Tianjin Enterprise Science and Technology Commissioner Project (18JCTPJC59400 to XG). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: The use of human biological materials (Number: YB M-05-02) was approved by the Use Ethics Committee of Shanghai Outdo Biotech Company.