title: Biallelic inactivation of protoporphyrinogen oxidase and hydroxymethylbilane synthase is associated with liver cancer in acute porphyrias.
abstract: Variegate porphyria (VP) and acute intermittent porphyria (AIP), the two most common types of acute porphyrias (AHPs), result from a partial deficiency of protoporphyrinogen oxidase (PPOX) and hydroxymethylbilane synthase (HMBS), respectively. A rare but serious complication in the AHPs is hepatocellular carcinoma (HCC). However, the underlying pathomechanisms are yet unknown. We performed DNA sequence analysis in cancerous and non-cancerous liver tissue of a VP and an AIP patient, both with HCC. In samples of both cancerous and non-cancerous liver tissues from the patients, we identified the underlying PPOX and HMBS germline mutations, c.1082dupC and p.G111R, respectively. Additionally, we detected a second somatic mutation, only in the cancer tissue i.e., p.L416X in the PPOX gene of the VP patient and p.L220X in the HMBS gene of the AIP patient, both located in trans to the respective germline mutations. Both somatic mutations were not detected in 10 non-porphyria-associated HCCs. Our data demonstrate that in the hepatic cancer tissue of AHP patients, somatic second-hit mutations result in nearly complete inactivation of the enzymes catalyzing major steps in the heme biosynthetic pathway. Both PPOX and HMBS, which might act as tumor suppressors, play a crucial role in the development of HCC in these individuals.
authors.affiliation: Institute of Laboratory Medicine and Swiss Porphyrin Reference Laboratory, Stadtspital Triemli, Zürich, Switzerland.
authors.forename: Xiaoye
authors.initials: X
authors.lastname: Schneider-Yin
authors.affiliation: Department of Dermatology, Maastricht University Medical Center (MUMC), The Netherlands; GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), The Netherlands.
authors.forename: Anne-Moon
authors.initials: AM
authors.lastname: van Tuyll van Serooskerken
authors.affiliation: Department of Dermatology and Skin Cancer Center and European Porphyria Specialist Center, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Marko
authors.initials: M
authors.lastname: Siegesmund
authors.affiliation: Institute of Pathology Enge, Zürich, Switzerland.
authors.forename: Philip
authors.initials: P
authors.lastname: Went
authors.affiliation: Institute of Laboratory Medicine and Swiss Porphyrin Reference Laboratory, Stadtspital Triemli, Zürich, Switzerland.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Barman-Aksözen
authors.affiliation: Department of Dermatology, Maastricht University Medical Center (MUMC), The Netherlands; GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), The Netherlands.
authors.forename: Reno S
authors.initials: RS
authors.lastname: Bladergroen
authors.affiliation: Institute of Pathology, Stadtspital Triemli, Zürich, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Komminoth
authors.affiliation: Department of Pathology, Maastricht University Medical Center (MUMC), The Netherlands.
authors.forename: Roy H E
authors.initials: RH
authors.lastname: Cloots
authors.affiliation: Department of Pathology, Maastricht University Medical Center (MUMC), The Netherlands.
authors.forename: Véronique J
authors.initials: VJ
authors.lastname: Winnepenninckx
authors.affiliation: Department of Pathology, Maastricht University Medical Center (MUMC), The Netherlands.
authors.forename: Axel
authors.initials: A
authors.lastname: zur Hausen
authors.affiliation: Department of Surgery, Stadtspital Triemli, Zürich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Weber
authors.affiliation: Department of Pathology, Maastricht University Medical Center (MUMC), The Netherlands.
authors.forename: Ann
authors.initials: A
authors.lastname: Driessen
authors.affiliation: Department of Dermatology, Annadal Medical Center Maastricht, The Netherlands; Department of Dermatology, Ziekenhuis Oost-Limburg (ZOL) Genk, Belgium.
authors.forename: Pamela
authors.initials: P
authors.lastname: Poblete-Gutiérrez
authors.affiliation: Department of Medical Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.affiliation: Department of Medical Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Schroeder
authors.affiliation: Department of Dermatology, Maastricht University Medical Center (MUMC), The Netherlands; GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), The Netherlands.
authors.forename: Michel
authors.initials: M
authors.lastname: van Geel
authors.affiliation: Institute of Laboratory Medicine and Swiss Porphyrin Reference Laboratory, Stadtspital Triemli, Zürich, Switzerland.
authors.forename: Elisabeth I
authors.initials: EI
authors.lastname: Minder
authors.affiliation: Department of Dermatology, Maastricht University Medical Center (MUMC), The Netherlands; GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), The Netherlands; Department of Dermatology and Skin Cancer Center and European Porphyria Specialist Center, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany. Electronic address: jorge.frank@med.uni-duesseldorf.de.
authors.forename: Jorge
authors.initials: J
authors.lastname: Frank
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000209:etiology* / Q000235:genetics*; D005260:Female; D005420:Flavoproteins / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D008113:Liver Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation; D017118:Porphyria, Acute Intermittent / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D046350:Porphyria, Variegate / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D050768:Protoporphyrinogen Oxidase / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D005420:Flavoproteins; D024101:Mitochondrial Proteins; D025521:Tumor Suppressor Proteins; C493978:PPOX protein, human; D050768:Protoporphyrinogen Oxidase; D011163:Hydroxymethylbilane Synthase
keywords: Acute intermittent porphyria; Hepatocellular carcinoma; Tumor suppressor; Variegate porphyria