Thomas Haverkamp1, Olivia Bronisch2, Thomas Knösel3, Carolin Mogler4, Wilko Weichert4, Thomas Stauch5, Claudia Schmid6, Claudia Rummeny7, Maria K Beykirch2, Petro E Petrides8. 1. Molecular Genetics Laboratory, MVZ Dr.Eberhard, Brauhausstr.4, 44137, Dortmund, Germany. 2. Hematology Oncology Center, EPNET Clinical Center Munich, Ludwig Maximilians University (LMU) Munich, Zweibrückenstr.2, 80331, Munich, Germany. 3. Institute of Pathology, Ludwig Maximilians University Munich (LMU), Thalkirchner Str.36, 80337, Munich, Germany. 4. Institute of Pathology, Klinikum Rechts Der Isar (RDI), Technical University of Munich, Trogerstr.36, 80337, Munich, Germany. 5. EPNET-Porphyria Specialist Laboratory MVZ PD Dr, Volkmann Kriegsstraße 99, 76133, Karlsruhe, Germany. 6. Institute of Radiology Dachau, Frühlingstr.33-34, 85221, Dachau, Germany. 7. Institute of Radiology Munich East, Wasserburger Landstr.274-276, 81827, Munich, Germany. 8. Hematology Oncology Center, EPNET Clinical Center Munich, Ludwig Maximilians University (LMU) Munich, Zweibrückenstr.2, 80331, Munich, Germany. petrides@onkologiemuenchen.de.
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.
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.
Authors: Janice Onuki; Priscila C Teixeira; Marisa H G Medeiros; Dieter Dörnemann; Thierry Douki; Jean Cadet; Paolo Di Mascio Journal: Cell Mol Biol (Noisy-le-grand) Date: 2002-02 Impact factor: 1.770