Ahmed, Fowsiyo Y

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, increasingly arising in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Epigenetic dysregulation, particularly DNA methylation, has been implicated in MASLD-HCC development, yet the roles that the principal DNA methylation precursor metabolites, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), play in this association are unclear. Objective: We investigated associations of circulating SAM, SAH, the SAM/SAH ratio, with MASLD-HCC. Methods: In a multi-center pilot case–control study, we evaluated 69 MASLD-HCC cases and 136 cancer-free MASLD controls. Plasma SAM and SAH levels were quantified by liquid chromatography–tandem mass spectrometry. Metabolite levels were categorized as greater than or less than the median based on distribution in controls. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, body mass index, smoking status, and type 2 diabetes. Results: MASLD-HCC cases had significantly higher plasma SAM levels (mean 121 vs. 96 nmol/L; p = 0.001) and SAM/SAH ratios (2.09 vs. 1.48; p = 6.42 × 10−7) than MASLD controls. In multivariable-adjusted models, elevated SAM levels (OR≥median vs. <median = 2.76; 95% CI: 1.38–5.72) and higher SAM/SAH ratio (OR≥median vs. <median = 2.30; 95% CI: 1.15–4.73) were associated with higher odds of MASLD-HCC. SAH alone was associated with MASLD-HCC. Conclusions: Higher plasma SAM levels and SAM/SAH ratios are independently linked to MASLD-HCC development. These metabolites might serve as noninvasive markers for HCC risk stratification in patients with MASLD and improve early detection efforts for MASLD-HCC.

Cholangiocarcinoma (CCA), the second most common primary liver tumor, is associated with a dismal outcome, and useful prognostic markers are not currently available in clinical practice. SerpinB3, a serine protease inhibitor, was recently found to play a relevant role in malignant transformation in different cancers. The aim of the present study was to determine the expression of SerpinB3/4 in tissue and serum samples of patients with CCA in relation to clinical outcomes. SerpinB3/4 was assessed in the tissue microarrays (TMAs) of 123 surgically resected CCAs. ELISA assays were carried out in 188 patients with CCA to detect the free and IgM-linked forms of SerpinB3/4. Overall survival was analyzed in relation to SerpinB3/4 expression, and Cox models were used to identify the variables associated with survival. High levels of SerpinB3/4 (TMA score 2+/3+) were detected in 15 tumors (12.2%), characterized by a more advanced TNM stage (III/IV: 64.3% vs. 31.3%; p = 0.031) and lower overall patient survival, independently of CCA subclass (intrahepatic CCA: median 1.1 (0.8—Not Estimable, NE) vs. 2.4 (1.8–3.4) years; p = 0.0007; extrahepatic CCA: median 0.8 (0.2—NE) vs. 2.2 (1.5–5.4) years; p = 0.011). Vascular invasion (p = 0.027) and SerpinB3/4 scores (p = 0.0016) were independently associated with mortality in multivariate analysis. Patients who had detectable free or IgM-linked SerpinB3/4 in their serum showed poorer survival (1 vs. 2.4 years, p = 0.015, for free SerpinB3/4, and 1 vs. 2.6 years, p = 0.0026, for SerpinB3/4–IgM). In conclusion, high levels of SerpinB3/4 in tissue and serum in CCA are associated with poor outcomes after surgery, regardless of tumor subclass.