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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We thank Jane and Michael Waldmann for proofreading the manuscript.
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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.
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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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DOI: https://doi.org/10.1007/s00432-022-04384-5