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Heterogeneous molecular behavior in liver tumors (HCC and CCA) of two patients with acute intermittent porphyria

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Abstract

Introduction

Acute intermittent porphyria (AIP) is a very rare (orphan) metabolic disorder of porphyrin biosynthesis which is characterized by elevated plasma and urine levels of 5-aminolevulinic acid (5-ALA) and porphobilinogen (PBG). Patients with this disorder which is caused by a germline mutation of the hydroxymethylbilan-synthase (HMBS)-gene have a high risk of primary liver cancer which may be determined by disease activity. The exact mechanism of carcinogenesis of this rare tumor is unknown, however.

Materials and methods

We analyzed paraffin-embedded formalin-fixed liver tumor and normal liver specimens of two female AIP patients treated at the Munich EPNET center. One patient had developed hepatocellular carcinoma (HCC), the other intrahepatic cholangiocarcinoma (CCA). Since biallelic inactivation of HMBS had been observed in one study, we used Sanger and next-generation sequencing with a 8 gene porphyria panel plus 6 potential modifier loci to search for mutations in DNA extractions.

Results

In the patient with the HCC, we found a second inactivating mutation in the HMBS gene in the tumor but not in the adjacent normal liver tissue. No mutation could be found in the liver tissues of the patient with CCA, however.

Conclusions

Biallelic inactivation of HMBS or protoporphyrinogen-oxidase (PPOX), another enzyme of porphyrin biosynthesis, has been observed in patients with acute porphyrias and liver tumors. We could confirm this in our patient with HCC with a mutation in HMBS but not in the one with CCA. Since 5-ALA can be converted into carcinogenic substances such as 4,5-dioxovaleric acid (DOVA) or 3,6-dihydropyrazine-2,5-dipropanoic acid (= cyclic dimerization product of 5-ALA), local production of these metabolites in hepatic areas with complete loss of HMBS activity may contribute to liver carcinogenesis.

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Availability of data and materials

The data that support the finding of study are available from the corresponding author upon request.

Abbreviations

AIP:

Acute intermittent porphyria

CCA:

Cholangiocarcinoma

5-ALA:

5-Aminolevulinic acid

DOVA:

4,5-Dioxovaleric acid

HCC:

Hepatocellular carcinoma

HMBS:

Hydroxymethylbilan-synthase (also called porphobilinogen-deaminase)

NGS:

Next-generation sequencing

PPOX:

Protoporphyrinogen-oxidase

ROI:

Regions of interest

TACE:

Transarterial chemoembolization

VAF:

Variant allele frequency

VP:

Variegate porphyria

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Acknowledgements

We thank Jane and Michael Waldmann for proofreading the manuscript.

Funding

From institutional funds.

Author information

Authors and Affiliations

  1. Molecular Genetics Laboratory, MVZ Dr.Eberhard, Brauhausstr.4, 44137, Dortmund, Germany

    Thomas Haverkamp

  2. Hematology Oncology Center, EPNET Clinical Center Munich, Ludwig Maximilians University (LMU) Munich, Zweibrückenstr.2, 80331, Munich, Germany

    Olivia Bronisch, Maria K. Beykirch & Petro E. Petrides

  3. Institute of Pathology, Ludwig Maximilians University Munich (LMU), Thalkirchner Str.36, 80337, Munich, Germany

    Thomas Knösel

  4. Institute of Pathology, Klinikum Rechts Der Isar (RDI), Technical University of Munich, Trogerstr.36, 80337, Munich, Germany

    Carolin Mogler & Wilko Weichert

  5. EPNET-Porphyria Specialist Laboratory MVZ PD Dr, Volkmann Kriegsstraße 99, 76133, Karlsruhe, Germany

    Thomas Stauch

  6. Institute of Radiology Dachau, Frühlingstr.33-34, 85221, Dachau, Germany

    Claudia Schmid

  7. Institute of Radiology Munich East, Wasserburger Landstr.274-276, 81827, Munich, Germany

    Claudia Rummeny

Authors
  1. Thomas Haverkamp
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  2. Olivia Bronisch
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  4. Carolin Mogler
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  6. Thomas Stauch
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  9. Maria K. Beykirch
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  10. Petro E. Petrides
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Contributions

PEP designed and supervised the study. TH did the molecular analyses, TK, WW, and CM carried out the pathological analyses, TS performed the biochemical analyses, CS and CR did the radiographies, and OB, MB and PEP were involved in patient care.

Corresponding author

Correspondence to Petro E. Petrides.

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Conflict of interest

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The study was approved in accordance with the Declaration of Helsinki and approved by the institutional review board of LMU Medical School.

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Patients or their families provided consent.

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Patients or their families provided consent.

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Haverkamp, T., Bronisch, O., Knösel, T. et al. Heterogeneous molecular behavior in liver tumors (HCC and CCA) of two patients with acute intermittent porphyria. J Cancer Res Clin Oncol 149, 2647–2655 (2023). https://doi.org/10.1007/s00432-022-04384-5

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