ArticleJournal of hepatology2022
Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma.
Article in Journal of hepatology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 34 citations in OpenAlex.
- Hepatocellular Carcinoma in Acute Hepatic Porphyria: A Meta-Analysis of Observational Studies.Digestive diseases and sciences · 2024Pooled it
- Air pollution and hepatocellular carcinoma: Integrated network toxicology, machine learning, molecular docking and multiomics analysis.Oncology letters · 2026Article
- Integrated genomic analyses identify oncogenic pathway interplay in hepatocarcinogenesis defining specific molecular subtypes.Nature communications · 2026Article
- Enzyme-Integrated Hydrogels for Advanced Biological Applications.Polymer science & technology (Washington, D.C.) · 2026Review
- Biallelic pathogenic hydroxymethylbilane synthase gene variants of a neurodegenerative disorder with progressive cystic leukoencephalopathy: a case report.Journal of medical case reports · 2026Article
- Porphyrias: Pathophysiology and clinical management recommendations for hepatologists.Hepatology communications · 2025Review
- Probiotic Mixture Attenuates Colorectal Tumorigenesis in Murine AOM/DSS Model by Suppressing STAT3, Inducing Apoptotic p53 and Modulating Gut Microbiota.Probiotics and antimicrobial proteins · 2025Article
- Article
- Liver transplantation and primary liver cancer in porphyria.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Analysis of clinical significance and molecular characteristics of methionine metabolism and macrophage-related patterns in hepatocellular carcinoma based on machine learning.Cancer biomarkers : section A of Disease markers · 2024Article
- Transcriptomics of MASLD Pathobiology in African American Patients in the Washington DC AreaInternational journal of molecular sciences · 2023Article
- Article
- Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation.American journal of human genetics · 2023Article
- Nutritional Interventions withInternational journal of molecular sciences · 2023Article
- Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma.Nature communications · 2023Article
- Heterogeneous molecular behavior in liver tumors (HCC and CCA) of two patients with acute intermittent porphyria.Journal of cancer research and clinical oncology · 2023Review
- Discovering cryptic splice mutations in cancers via a deep neural network framework.NAR cancer · 2023Article
- Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation.bioRxiv : the preprint server for biology · 2023Article
- Characterization of the microenvironment in different immune-metabolism subtypes of cervical cancer with prognostic significance.Frontiers in genetics · 2023Article
- Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment.Life (Basel, Switzerland) · 2022Review
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11 authors at 6 institutions in 3 countries.
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Abstract
BACKGROUND &
aimsAcute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers a high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear.
methodsHerein, we explore HMBS alterations in a large series of 758 HCC cases, including 4 patients with AIP. We quantify the impact of HMBS mutations on heme biosynthesis pathway intermediates and we investigate the molecular and clinical features of HMBS-mutated tumors.
resultsWe identify recurrent bi-allelic HMBS inactivation, both in patients with AIP acquiring a second somatic HMBS mutation and in sporadic HCC with 2 somatic hits. HMBS alterations are enriched in truncating mutations, in particular in splice regions, leading to abnormal transcript structures. Bi-allelic HMBS inactivation results in a massive accumulation of its toxic substrate porphobilinogen and synergizes with CTNNB1-activating mutations, leading to the development of well-differentiated tumors with a transcriptomic signature of Wnt/β-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affects females, in the absence of fibrosis and classical HCC risk factors.
conclusionsThese data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype. LAY SUMMARY: Heme (the precursor to hemoglobin, which plays a key role in oxygen transport around the body) synthesis occurs in the liver and involves several enzymes including hydroxymethylbilane synthase (HMBS). HMBS mutations cause acute intermittent porphyria, a disease caused by the accumulation of toxic porphyrin precursors. Herein, we show that HMBS inactivation is also involved in the development of liver cancers with distinct clinical and molecular characteristics.
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