👤 Sayuri Nitta

The mechanism of hepatocarcinogenesis after sustained virological response (SVR) in hepatitis C virus (HCV) patients is unclear. We compared gene profiles of hepatocellular carcinoma (HCC) between HCV-SVR, steatotic liver disease (SLD), and HCV-non-SVR patients. This study analyzed 126 resected HCCs from patients with HCV and SLD, classifying them as HCV-SVR (n = 22), HCV-non-SVR (n = 56), and SLD (n = 48). Deep sequencing of 2910 hotspots in 55 cancer-related genes was conducted to examine mutations and copy number variations in both cancerous and background liver tissues. The HCV-SVR group comprised more patients who consumed alcohol (45.5% vs. 15.7%, p = 0.008), were obese (54.5% vs. 17.9%, p = 0.002), and had dyslipidemia (18.2% vs. 3.6%, p = 0.029) and hyperuricemia (18.2% vs. 3.6%, p = 0.029) than the HCV-non-SVR group. Mutational profiling of the HCV-SVR HCC showed significantly lower alteration rates of AXIN1 (13.6% vs. 42.9%, p = 0.016), ARID2 (9.1% vs. 39.3%, p = 0.013), and TP53 (9.1% vs. 32.1%, p = 0.030) than HCV-non-SVR patients. Compared with HCV-non-SVR-HCC, SLD-HCCs showed significantly lower rates of TERT promoter mutations (62.5% vs. 85.7%, p = 0.004), ARID2 alterations (12.5% vs. 39.3%, p = 0.003), and AXIN1 alterations (12.5% vs. 42.9%, p = 0.002). HCV-SVR/MASH/MASLD/ALD-HCC had significantly lower alteration rates of the Wnt/β-catenin (41.4% vs. 60.7%, p = 0.048) and chromatin remodeling pathways (27.1% vs. 48.2%, p = 0.026) than HCV-non-SVR-HCC. HCV-SVR HCC is linked to alcohol use and metabolic diseases, showing a mutational profile similar to SLD-HCC. Show less

Long-term survival of patients with neonatal-onset carbamoyl-phosphate synthetase 1 deficiency (CPS1D), an autosomal recessive disorder characterized by repeated, life-threatening hyperammonemia, is rare. We describe the diagnosis and clinical management of a teenager with neonatal-onset CPS1D who did not undergo therapeutic liver transplantation. Following emergent neonatal therapy, the patient was diagnosed with CPS1D based on clinical, radiological, biochemical and genetic analyses. Her clinical course, neurobehavioral development and therapeutic interventions are presented and discussed. Born from nonconsanguineous parents, the proband underwent phototherapy for neonatal jaundice, associated with acute encephalopathy, apnea and cerebral edema. Based on blood and urinary biochemical abnormalities, neonatal-onset CPS1D was diagnosed. Her hyperammonemia was corrected by hemodialysis, followed by sodium benzoate, L-arginine, levocarnitine and protein-free diet therapy. Because of a relapse and persistent neurobehavioral regression by age 1, a planned liver transplantation was cancelled. At age 10, sodium phenylbutyrate was substituted as ammonia scavenger. Genetic testing revealed compound heterozygote c.2359C>T (R787X) and c.236+6T>C variants of CPS1, confirming her diagnosis. Despite severe neurological sequelae, the patient is 16 and in stable condition. Our case suggests that early hemodialysis and pharmacologic interventions for acute neonatal hyperammonemia can improve the prognosis of patients with neonatal-onset CPS1D. Show less

Genetic alterations in specific genes are critical events in carcinogenesis and hepatocellular carcinoma (HCC) progression. However, the genetic alterations responsible for HCC development, progression, and survival are unclear. We investigated the essential difference in genetic alterations between HCC and adjacent non-HCC tissues using next-generation sequencing technology. We found recurrent mutations in several genes such as telomerase reverse transcriptase (TERT; 65% of the total 104 HCCs), TP53 (38%), CTNNB1 (30%), AXIN1 (2%), PTEN (2%), and CDKN2A (2%). TERT promoter mutations were associated with older age (p = 0.005), presence of hepatitis C virus (HCV) infection (p = 0.003), and absence of hepatitis B virus (HBV) infection (p < 0.0001). In hepatitis B surface antigen (HBs Ag)-positive HCC without TERT promoter mutations, HBV integration into TERT locus was found in 47% patients and was mutually exclusive to TERT promoter mutations. Most (89%) HBV integrants were in the HBx region. TP53 mutations were associated with HBV infection (p = 0.0001) and absence of HCV infection (p = 0.002). CTNNB1 mutations were associated with absence of HBV infection (p = 0.010). Moreover, TERT promoter mutation was significantly associated with shorter disease-free survival (p = 0.005) and poor overall survival (p = 0.024). Gene alterations in TERT promoter, TP53, CTNNB1, and HBV integration were closely associated with HCC development, and mutations in TERT promoter are related to poor prognosis. These results are useful for understanding the underlying mechanism of hepatocarcinogenesis, diagnosis, and predicting outcomes of patients with HCC. Show less