Heterogeneous molecular behavior in liver tumors (HCC and CCA) of two patients with acute intermittent porphyria.
4,5-Dioxovaleric acid
5-ALA
Acute porphyria
Biallelic inactivation
Cholangiocarcinoma
HMBS activity
Hepatocellular carcinoma
Journal
Journal of cancer research and clinical oncology
ISSN: 1432-1335
Titre abrégé: J Cancer Res Clin Oncol
Pays: Germany
ID NLM: 7902060
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
received:
02
06
2022
accepted:
26
09
2022
medline:
27
4
2023
pubmed:
17
10
2022
entrez:
16
10
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 36245063
doi: 10.1007/s00432-022-04384-5
pii: 10.1007/s00432-022-04384-5
doi:
Substances chimiques
Aminolevulinic Acid
88755TAZ87
Flavoproteins
0
Mitochondrial Proteins
0
Porphyrins
0
PPOX protein, human
EC 1.3.3.4
Protoporphyrinogen Oxidase
EC 1.3.3.4
Types de publication
Case Reports
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
2647-2655Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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