Highlights
- •We identify recurrent HMBS-inactivating mutations in hepatocellular carcinoma.
- •Bi-allelic HMBS inactivation occurs both in patients with acute intermittent porphyria and sporadic HCC.
- •HMBS inactivation induces a massive accumulation of its toxic substrate porphobilinogen.
- •HMBS-mutated HCC mostly develop in females, in the absence of fibrosis and classical HCC risk factors.
- •HMBS-mutated HCC display activating CTNNB1 mutations and Wnt/β-catenin pathway activation.
Background & Aims
Acute 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.
Methods
Herein, 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.
Results
We 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.
Conclusions
These 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.
Graphical abstract
Graphical Abstract
Keywords
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References
- Hepatocellular carcinoma.Nat Rev Dis Primers. 2021; 7: 1-28https://doi.org/10.1038/s41572-020-00240-3
- Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation.Gastroenterology. 2017; 152: 880-894.e6https://doi.org/10.1053/j.gastro.2016.11.042
- Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress.Nat Commun. 2018; 9: 5235https://doi.org/10.1038/s41467-018-07552-9
- Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.Nat Genet. 2015; 47: 505-511https://doi.org/10.1038/ng.3252
- Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.Nat Genet. 2016; 48: 500-509https://doi.org/10.1038/ng.3547
- Comprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell. 2017; 169: 1327-1341.e23https://doi.org/10.1016/j.cell.2017.05.046
- Genetic landscape and biomarkers of hepatocellular carcinoma.Gastroenterology. 2015; 149: 1226-1239.e4https://doi.org/10.1053/j.gastro.2015.05.061
- Discovery and saturation analysis of cancer genes across 21 tumour types.Nature. 2014; 505: 495-501https://doi.org/10.1038/nature12912
- The epidemiology of hepatocellular carcinoma in patients with acute intermittent porphyria.J Intern Med. 1996; 240: 195-201https://doi.org/10.1046/j.1365-2796.1996.21847000.x
- Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden.Am J Epidemiol. 1999; 149: 1010-1015https://doi.org/10.1093/oxfordjournals.aje.a009745
- Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors.J Hepatol. 2000; 32: 933-939https://doi.org/10.1016/s0168-8278(00)80097-5
- Screening for hepatocellular carcinoma in acute intermittent porphyria: a 15-year follow-up in northern Sweden.J Intern Med. 2011; 269: 538-545https://doi.org/10.1111/j.1365-2796.2010.02335.x
- High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria.J Inherit Metab Dis. 2013; 36: 1063-1071https://doi.org/10.1007/s10545-012-9576-9
- Hepatocellular carcinoma in acute hepatic porphyrias: a Damocles Sword.Mol Genet Metab. 2019; 128: 236-241https://doi.org/10.1016/j.ymgme.2018.10.001
- Hepatocellular carcinoma in acute hepatic porphyrias: results from the longitudinal study of the U.S. Porphyrias Consortium.Hepatology. 2021; 73: 1736-1746https://doi.org/10.1002/hep.31460
Meyer UA, Strand LJ, Doss M, Rees AC, Marver HS. Intermittent acute porphyria — demonstration of a genetic defect in porphobilinogen metabolism. Https://Doi-OrgProxyInsermbiblioInistFr/101056/NEJM197206152862401 2010. https://doi.org/10.1056/NEJM197206152862401.
- Porphyrias.The Lancet. 2010; 375: 924-937https://doi.org/10.1016/S0140-6736(09)61925-5
- Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538https://doi.org/10.1111/bjh.14459
- Acute intermittent porphyria: prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France.J Intern Med. 1997; 242: 213-217https://doi.org/10.1046/j.1365-2796.1997.00189.x
- Acute intermittent porphyria: predicted pathogenicity of HMBS variants indicates extremely low penetrance of the autosomal dominant disease.Hum Mutat. 2016; 37: 1215-1222https://doi.org/10.1002/humu.23067
- Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs).Mol Genet Metab. 2019; 128: 213-218https://doi.org/10.1016/j.ymgme.2019.03.002
- Variations in porphobilinogen and 5-aminolevulinic acid concentrations in plasma and urine from asymptomatic carriers of the acute intermittent porphyria gene with increased porphyrin precursor excretion.Clin Chem. 2006; 52: 701-707https://doi.org/10.1373/clinchem.2005.058198
- Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks.Eur J Intern Med. 2009; 20: 201-207https://doi.org/10.1016/j.ejim.2008.06.012
- Risk of primary liver cancer in acute hepatic porphyria patients: a matched cohort study of 1244 individuals.J Intern Med. 2022; https://doi.org/10.1111/joim.13463
- Acute hepatic porphyria and hepatocellular carcinoma.Br J Cancer. 1988; 57: 117-120https://doi.org/10.1038/bjc.1988.23
- Biallelic inactivation of protoporphyrinogen oxidase and hydroxymethylbilane synthase is associated with liver cancer in acute porphyrias.J Hepatol. 2015; 62: 734-738https://doi.org/10.1016/j.jhep.2014.11.029
- Mutational heterogeneity in cancer and the search for new cancer-associated genes.Nature. 2013; 499: 214-218https://doi.org/10.1038/nature12213
- The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.Hum Genet. 2020; 139: 1197-1207https://doi.org/10.1007/s00439-020-02199-3
- DNA methylation signatures reveal the diversity of processes remodeling hepatocellular carcinoma methylomes.Hepatology. 2021; 74: 816-834https://doi.org/10.1002/hep.31796
- β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma.Cancer Discov. 2019; 9: 1124-1141https://doi.org/10.1158/2159-8290.CD-19-0074
- From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria.Hum Mol Genet. 2018; 27: 1164-1173https://doi.org/10.1093/hmg/ddy030
- Acute porphyrias: pathogenesis of neurological manifestations.Semin Liver Dis. 1998; 18: 43-52https://doi.org/10.1055/s-2007-1007139
- Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukemia cells.Cell Death Discov. 2019; 5: 77https://doi.org/10.1038/s41420-019-0157-7
- Protoporphyrin IX interacts with wild-type p53 protein in vitro and induces cell death of human colon cancer cells in a p53-dependent and -independent manner.J Biol Chem. 2007; 282: 2466-2472https://doi.org/10.1074/jbc.M608906200
- The multifaceted role of heme in cancer.Front Oncol. 2019; 9: 1540https://doi.org/10.3389/fonc.2019.01540
- Acute intermittent porphyria: clinical and selected research aspects.Ann Intern Med. 1975; 83: 851-864https://doi.org/10.7326/0003-4819-83-6-851
- LHRH analogues for hormonal manipulation in acute intermittent porphyria.Semin Hematol. 1989; 26: 10-15
- The induction in vitro of the synthesis of delta-aminolevulinic acid synthetase in chemical porphyria: a response to certain drugs, sex hormones, and foreign chemicals.J Biol Chem. 1966; 241: 1359-1375
Anderson KE, Spitz IM, Sassa S, Bardin CW, Kappas A. Prevention of cyclical attacks of acute intermittent porphyria with a long-acting agonist of luteinizing hormone–releasing hormone. Http://DxDoiOrg/101056/NEJM198409063111006 2010. https://doi.org/10.1056/NEJM198409063111006.
- Loss of hepatocyte β-catenin protects mice from experimental porphyria-associated liver injury.J Hepatol. 2019; 70: 108-117https://doi.org/10.1016/j.jhep.2018.09.023
- Zonation of heme synthesis enzymes in mouse liver and their regulation by β-catenin and Ha-ras.Biol Chem. 2010; 391: 1305-1313https://doi.org/10.1515/BC.2010.115
- Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674https://doi.org/10.1016/j.cell.2011.02.013
- The emerging hallmarks of cancer metabolism.Cell Metab. 2016; 23: 27-47https://doi.org/10.1016/j.cmet.2015.12.006
- An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812https://doi.org/10.1126/science.1164382
- Recurring mutations found by sequencing an acute myeloid leukemia genome.N Engl J Med. 2009; 361: 1058-1066https://doi.org/10.1056/NEJMoa0903840
- Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.Science. 2000; 287: 848-851https://doi.org/10.1126/science.287.5454.848
- Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families.Cancer Res. 2002; 62: 4554-4557
- An integrated computational and experimental study uncovers FUT9 as a metabolic driver of colorectal cancer.Mol Syst Biol. 2017; 13: 956https://doi.org/10.15252/msb.20177739
- Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis.Nat Commun. 2017; 8: 1315https://doi.org/10.1038/s41467-017-01358-x
- BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA.J Hepatol. 2020; 72: 924-936https://doi.org/10.1016/j.jhep.2019.12.006
- Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma.Gut. 2021; (gutjnl-2020-323153)https://doi.org/10.1136/gutjnl-2020-323153
- Macrotrabecular-massive hepatocellular carcinoma: a distinctive histological subtype with clinical relevance.Hepatology. 2018; 68: 103-112https://doi.org/10.1002/hep.29762
- Palimpsest: an R package for studying mutational and structural variant signatures along clonal evolution in cancer.Bioinformatics. 2018; 34: 3380-3381https://doi.org/10.1093/bioinformatics/bty388
- A high dose of isoniazid disturbs endobiotic homeostasis in mouse liver.Drug Metab Dispos. 2016; 44: 1742-1751https://doi.org/10.1124/dmd.116.070920
- The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria.Sci Adv. 2019; 5: eaaw6127https://doi.org/10.1126/sciadv.aaw6127
- Identification of novel pathways in idelalisib metabolism and bioactivation.Chem Res Toxicol. 2018; 31: 548-555https://doi.org/10.1021/acs.chemrestox.8b00023
- Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.Hepatology. 2007; 45: 42-52https://doi.org/10.1002/hep.21467
- Clinical impact of genomic diversity from early to advanced hepatocellular carcinoma.Hepatology. 2020; 71: 164-182https://doi.org/10.1002/hep.30811
- Analysis of liver cancer cell lines identifies agents with likely efficacy against hepatocellular carcinoma and markers of response.Gastroenterology. 2019; 157: 760-776https://doi.org/10.1053/j.gastro.2019.05.001
Article info
Publication history
Published online: May 27, 2022
Accepted:
May 10,
2022
Received in revised form:
April 22,
2022
Received:
February 2,
2022
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
