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Published on: May 24, 2024
Hepatocellular carcinoma after a sustained virological response by direct-acting antivirals harbors TP53 inactivation
Taisuke Imamura1, Yukiyasu Okamura1,2, Keiichi Ohshima3
1Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.
Introduction:
The genomic characteristics of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) and its differences according to whether an SVR was achieved by treatment with direct-acting antivirals (DAA) or interferon (IFN) are still not fully understood.
Methods:
Sixty-nine surgically resected HCCs from patients with hepatitis C virus infection were analyzed by gene expression profiling and whole-exome sequencing.
Results:
Among the 69 HCC patients, 34 HCCs in which an SVR was not achieved at the time of surgery were classified as HCV-positive, and 35 HCCs in which an SVR was achieved at the time of surgery were classified as HCV-SVR. According to the HCV treatment, 35 HCV-SVR HCCs were classified into two groups: eight tumors with DAA (HCV-SVR-DAA) and 24 tumors with interferon (HCV-SVR-IFN). The frequency of samples with ARID2 mutations was significantly lower in HCV-SVR than in HCV-positive tumors (p = 0.048). In contrast, the frequency of samples with PREX2 mutations was significantly higher in HCV-SVR samples than in HCV-positive samples (p = 0.048). Among the patients with HCV-SVR, the frequency of samples with TP53 mutations was significantly higher in HCV-SVR-DAA tumors than in HCV-SVR-IFN tumors (p = 0.030). TP53 inactivation scores in HCV-SVR-DAA tumors were found to be significantly enhanced in comparison to HCV-SVR-IFN tumors (p = 0.022). In addition, chromosomal instability and PI3K/AKT/mTOR pathway signatures were enhanced in HCV-SVR-DAA tumors. HCV-SVR-DAA was significantly associated with portal vein invasion (p = 0.003) in comparison to HCV-SVR-IFN.
Conclusion:
Our dataset potentially serves as a fundamental resource for the genomic characteristics of HCV-SVR-DAA tumors. Our comprehensive genetic profiling by WES revealed significant differences in the mutation rate of several driver genes between HCV-positive tumors and HCV-SVR tumors. Furthermore, it was revealed that the frequency of samples with mutations in TP53 was significantly higher in HCV-SVR-DAA tumors than in HCV-SVR-IFN tumors.
Insights
Hepatocellular carcinoma (HCC) genomics differ based on sustained virological response (SVR) achieved via direct-acting antivirals (DAA) or interferon (IFN). TP53 mutations and chromosomal instability are more prevalent in DAA-treated HCC, indicating distinct genomic profiles.
Area of Science:
- Oncology
- Virology
- Genomics
Background:
- Hepatocellular carcinoma (HCC) genomic profiles after sustained virological response (SVR) are not fully understood.
- Differences in HCC genomics based on SVR treatment (direct-acting antivirals [DAA] vs. interferon [IFN]) require further investigation.
Purpose of the Study:
- To investigate the genomic characteristics of HCC in patients who achieved SVR after hepatitis C virus (HCV) infection.
- To compare the genomic differences in HCC tumors based on the type of SVR treatment received (DAA vs. IFN).
Main Methods:
- Gene expression profiling and whole-exome sequencing were performed on 69 surgically resected HCC samples from HCV-infected patients.
- HCC samples were categorized into HCV-positive (no SVR), HCV-SVR (SVR achieved), and further subgrouped into HCV-SVR-DAA and HCV-SVR-IFN based on treatment.
Main Results:
- Significantly lower ARID2 mutation frequency and higher PREX2 mutation frequency were observed in HCV-SVR tumors compared to HCV-positive tumors.
- HCV-SVR-DAA tumors showed a significantly higher frequency of TP53 mutations and enhanced TP53 inactivation scores compared to HCV-SVR-IFN tumors.
- Chromosomal instability and PI3K/AKT/mTOR pathway activation were enhanced in HCV-SVR-DAA tumors, which were also associated with portal vein invasion.
Conclusions:
- Genomic profiling reveals significant differences in driver gene mutation rates between HCV-positive and HCV-SVR HCC tumors.
- TP53 mutations are significantly more frequent in HCC tumors treated with DAA compared to those treated with IFN for achieving SVR.
- The study provides a genomic resource for understanding DAA-treated HCV-SVR HCC, highlighting distinct mutational patterns and pathway activations.
