HBV integrations reshaping genomic structures promote hepatocellular carcinoma.

OBJECTIVE: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further. DESIGN: Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice. RESULTS: These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials. CONCLUSION: HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.

Development and Validation of a Nomogram-Based Prognostic Evaluation Model for Sarcomatoid Hepatocellular Carcinoma.

INTRODUCTION: Sarcomatoid hepatocellular carcinoma (SHC) is a rare subtype of liver cancer with extremely poor prognosis. This study aimed to identify the prognostic factors and develop an exclusive and efficient nomogram to predict cancer-specific survival (CSS) for SHC. METHODS: The data on patients diagnosed with SHC from January 1973 to December 2015 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database, and these patients were included as the training cohort. Least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression analyses were used to identify the prognostic risk factors and construct a nomogram. The predictive accuracy and discriminative ability of the nomogram were determined using concordance index (C-index), calibration curve, and receiver operating characteristic (ROC) curve. Decision curve analysis (DCA) was used to compare the clinical benefits of the prognostic evaluation model (PEM) with that of the American Joint Committee on Cancer (AJCC) staging system. The results were validated with an external validation cohort. RESULTS: In total, 116 patients with SHC were included in the training cohort. Multivariate Cox analysis revealed M stage (distant metastasis), primary tumor surgery, and chemotherapy to be associated with CSS, and along with tumor size, an integrated PEM was constructed. A calibration curve for the probability of survival showed good agreement between the nomogram and actual observation. The C-index value of the nomogram for predicting CSS and AJCC was 0.853 and 0.649, respectively. In the validation cohort, the C-index value of the PEM discrimination was better than that of the Barcelona Clinic Liver Cancer (BCLC) staging system, CLIP score, and Okuda staging system, and no statistical difference was observed with eighth edition of the AJCC staging system and Izumi staging system. CONCLUSION: The proposed four-factor nomogram of PEM could accurately predict the prognosis of SHC and could be used in clinical practice.