Schnidrig, D. | bioRxiv Science

bioRxiv2025

Liver Zonation Disruption Fuels Hepatocellular Carcinoma in Chronic Liver Disease

Hepatocellular carcinoma (HCC) arises almost exclusively in chronic liver disease (CLD), yet the classical etiological drivers of injury insufficiently explain why only a subset of patients progress to cancer. Here, we identify disruption of liver metabolic zonation, specifically, aberrant expansion of {beta}-catenin activity from pericentral to periportal territories as a previously unrecognized tumorigenic risk state that emerges across etiologically diverse CLDs. Using spatial transcriptomics and immunohistochemistry from murine liver disease followed by human sample validation, we demonstrate that MASLD/MASH, alcohol-associated hepatitis, viral hepatitis, and immune-mediated cholangiopathies share a striking periportal induction of pericentral {beta}-catenin target programs, indicating a conserved zonation disturbance independent of disease etiology. Since {beta}-catenin expansion occurs alongside inflammation, fibrosis, and metabolic dysfunction in human CLD, its direct oncogenic contribution remained unclear. To functionally isolate the tumorigenic consequence of zonation disruption itself from these confounding disease processes, we employed hepatocyte-specific deletion of ZNRF3 and RNF43--negative regulators that physiologically restrict {beta}-catenin to the pericentral zone. Lineage tracing demonstrates that ZNRF3/RNF43 deletion drives selective periportal hepatocyte proliferation, zonal reprogramming, and tumor initiation in a {beta}-catenin-dependent manner, establishing zonation disruption as a direct mechanistic driver of carcinogenesis. The resulting tumors exhibit a distinct metabolic and immunologic phenotype, including heightened mitochondrial respiration, preserved periportal identity, and T-cell competence, and correspond to a molecularly defined subset comprising 5-10% of human HCCs. Together, these findings reveal {beta}-catenin zonation expansion as a conserved and previously unrecognized HCC risk factor that mechanistically links chronic liver injury to malignant transformation. They further establish ZNRF3/RNF43 deletion as a tractable model of zonation-driven hepatocarcinogenesis and identify a distinct human HCC subtype with unique therapeutic vulnerabilities, opening new avenues for mechanism-based risk stratification, early detection and preventive therapeutic strategies in patients with chronic liver disease.

cancer biology↗

bioRxiv2022

PipeIT2: A tumor-only somatic variant calling workflow for Molecular Diagnostic Ion Torrent sequencing data

Precision oncology relies on the accurate identification of somatic mutations in cancer patients. While the sequencing of the tumoral tissue is frequently part of routine clinical care, the healthy counterparts are rarely sequenced. We previously published PipeIT, a somatic variant calling workflow specific for Ion Torrent sequencing data enclosed in a Singularity container. PipeIT combines user-friendly execution, reproducibility and reliable mutation identification, but relies on matched germline sequencing data to exclude germline variants. Expanding on the original PipeIT, here we describe PipeIT2 to address the clinical need to define somatic mutations in the absence of germline control. We show that PipeIT2 achieves a >95% recall for variants with variant allele fraction >10%, reliably detects driver and actionable mutations and filters out most of the germline mutations and sequencing artifacts. With its performance, reproducibility and ease of execution, PipeIT2 is a valuable addition to molecular diagnostics laboratories.

bioinformatics↗