Background/Aims Liver transplantation (LT) following total hepatectomy is a life-saving treatment for hepatocellular carcinoma (HCC). The HCC recurrence after LT hinders the effectiveness of the procedure. The objective of this study is to develop a pre-operative risk stratification model based on a liquid biopsy.
Methods We conducted a comprehensive multi-omics study of 260 HCC patients from three centers, including clinical data, low-coverage whole-genome sequencing of cell-free DNA (cfDNA) from plasma, as well as whole-exome, single-nucleus RNA, and spatial transcriptomics from matched tumor and non-tumor tissues.
Results We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of specialized endothelial subtypes and cancer-associated fibroblasts. Notably, most recurrence-associated lesions were detectable in cfDNA prior to liver transplantation (LT). Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures, and validated it using internal and independent external cohorts.
Conclusion Our findings suggest that post-transplant recurrence commonly originates from advanced subclones that emerge late during tumor evolution. The ZJU Criteria provides an accurate, non-invasive strategy that significantly improves pre-LT risk stratification and clinical decision-making for patients with HCC.
Background/Aims Identifying patients with intrahepatic cholangiocarcinoma (ICC) likely to benefit from immunochemotherapy, the new front-line treatment, remains challenging. We aimed to unveil a novel radiotranscriptomic signature that can facilitate treatment response prediction by multi-omics integration and multiscale modelling.
Methods We analyzed bulk, single-cell and spatial transcriptomic data comprising 457 ICC patients to identify an immune-related score (IRS), followed by decoding its spatial immune context. We mapped radiomics profiles onto spatial-specific IRS using machine learning to define a novel radiotranscriptomic signature, followed by multi-scale and multi-cohort validation covering 331 ICC patients. The signature was further explored for the potential therapeutic target from in vitro to in vivo.
Results We revealed a novel 3-gene (PLAUR, CD40LG, and FGFR4) IRS whose down-regulation correlated with better survival and improved sensitivity to immunochemotherapy. We highlighted functional IRS-immune interactions within tumor epithelium, rather than stromal compartment, irrespective of geospatial locations. Machine learning pipeline identified the optimal 3-feature radiotranscriptomic signature that was well-validated by immunohistochemical assays in molecular cohort, exhibited favorable external prognostic validity with C-index over 0.64 in resection cohort, and predicted treatment response with an area under the curve of up to 0.84 in immunochemotherapy cohort. We also showed that anti-uPAR/PLAUR alone or in combination with anti-programmed cell death protein 1 therapy remarkably curbed tumor growth, using in vitro ICC cell lines and in vivo humanized ICC patient-derived xenograft mouse models.
Conclusions This proof-of-concept study sheds light on the spatially-resolved radiotranscriptomic signature to improve patient selection for emerging immunochemotherapy and high-order immunotherapy combinations in ICC.
Citations
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Background/Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by fat accumulation in the liver. MASLD encompasses both steatosis and MASH. Since MASH can lead to cirrhosis and liver cancer, steatosis and MASH must be distinguished during patient treatment. Here, we investigate the genomes, epigenomes, and transcriptomes of MASLD patients to identify signature gene set for more accurate tracking of MASLD progression.
Methods Biopsy-tissue and blood samples from patients with 134 MASLD, comprising 60 steatosis and 74 MASH patients were performed omics analysis. SVM learning algorithm were used to calculate most predictive features. Linear regression was applied to find signature gene set that distinguish the stage of MASLD and to validate their application into independent cohort of MASLD.
Results After performing WGS, WES, WGBS, and total RNA-seq on 134 biopsy samples from confirmed MASLD patients, we provided 1,955 MASLD-associated features, out of 3,176 somatic variant callings, 58 DMRs, and 1,393 DEGs that track MASLD progression. Then, we used a SVM learning algorithm to analyze the data and select the most predictive features. Using linear regression, we identified a signature gene set capable of differentiating the various stages of MASLD and verified it in different independent cohorts of MASLD and a liver cancer cohort.
Conclusions We identified a signature gene set (i.e., CAPG, HYAL3, WIPI1, TREM2, SPP1, and RNASE6) with strong potential as a panel of diagnostic genes of MASLD-associated disease.
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