Analyzing hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) expression and survival in patients with hepatocellular carcinoma (HCC) using cBioPortal.

Abstract

e16236 Background: The ketogenic diet (KD) has been shown to up-regulate the rate-limiting enzyme of ketogenesis (Lan, 2022), hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), which may play role in hepatocellular carcinoma (HCC) suppression when over-expressed (Cui, 2022). The open-source nature of cancer genomics websites like cBioPortal enables resource-constrained investigators the ability to engage with translational hypothesis generating research and is used here to explore the relationship between HMGCS2 expression and retrospective clinical data to guide future research. Methods: After selecting the PanCancer Atlas Liver Hepatocellular Carcinoma study for its patient-level data on both overall survival and tumor gene expression, the integrated cBioPortal query function was used to stratify the expression of HMGCS2 by over-expression (EXP > 1), under-expression (EXP < -1), or unaltered expression. The integrated survival analysis was used to generate Kaplan-Meier curves with hazard ratios derived from the long-rank test. Median overall survival (OS) and hazard ratios (HR) are reported with 95% confidence intervals. Results: 366 patients’ samples with HCC were analyzed with 73 (20%) of samples having alterations in HMGCS2 expression. 39 samples (11%) had HMGCS2 over-expression (EXP > 1), 34 (9%) were under-expressed (EXP < -1), and 292 samples had no expression alterations. Compared to the unaltered expression group with a median OS of 53.39 months (45.11-83.24), patients with HMGCS2 over-expression had a median OS of 70.06 (51.29 - NA) months for a HR of 0.592 (0.352 - 0.997). Patients with decreased expression of HMGCS2 had a median OS of 37.31 (13.48 - NA) with a HR of 1.367 (0.698 - 2.676) compared to patients with unaltered expression. Conclusions: This retrospective analysis of HMGCS2 expression in patients with HCC provides further support for the pre-clinical / translational research performed thus far with increased HMGCS2 expression associated with improved overall survival. Metabolic interventions targeting HMGCS2 expression such as the KD may warrant further investigation. Lan, Y., Jin, C., Kumar, P., Yu, X., Lenahan, C., & Sheng, J. (2022). Ketogenic Diets and Hepatocellular Carcinoma. Frontiers in Oncology , 12 , 879205. https://doi.org/10.3389/FONC.2022.879205 Cui, X., Yun, X., Sun, M., Li, R., Lyu, X., Lao, Y., Qin, X., & Yu, W. (2022). HMGCL-induced β-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility. Hepatology International , 17 (2), 377. https://doi.org/10.1007/S12072-022-10459-9.