Hepatocellular carcinoma in patients from northern Sweden with acute intermittent porphyria: morphology and mutations.
More than a decade ago an association between acute intermittent porphyria (AIP) and hepatocellular carcinoma (HCC) was reported, but still the cause of the increased prevalence is unknown. Paraffin sections of formalin-fixed HCC from 17 AIP patients were reexamined and also screened for relevant mutations using several methods. The tumor diagnosis was verified, and in several cases precirrhosis and cirrhosis were also found. The clinically founded AIP diagnosis was verified at the gene level in most cases, demonstrating the Norrland type of mutation, i.e., G(593)-to-A substitution in codon 198 of the porphobilinogen deaminase (PBGD) gene. The second allele was neither mutated nor missing, contradicting the possibility that the PBGD gene might function as a tumor suppressor gene. Subsequent sequencing showed that cases not cleaved by the restriction enzyme NheI lacked the specific Norrland mutation. In recent years, selective mutations at codons 249 and 166 of the p53 gene have been described in HCC associated with aflatoxin and hepatitis B virus. In our area, with low exposure to those agents, no mutations in codon 249 were found, and mutation in codon 166 was excluded in all tumors except one; no traces of hepatitis B DNA were observed. Nor did we find mutations in H-ras 12 or 61. Intrinsic aberrations in AIP, including reduced heme synthesis and endogenous oxidative damage to DNA, may incite carcinogenic mutations elsewhere in the genome of liver cells. The increased cell proliferation coupled to precirrhosis and cirrhosis perhaps represents promotion in the initiation-promotion sequence of hepatocarcinogenesis.
Bjersing
L
L
Department of Pathology, University Hospital, Umea, Sweden.
Andersson
C
C
Lithner
F
F
D000225:Adenine; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D002455:Cell Division / Q000235:genetics; D003062:Codon / Q000235:genetics; D004249:DNA Damage; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D005404:Fixatives; D005557:Formaldehyde; D016147:Genes, Tumor Suppressor / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006147:Guanine; D006418:Heme / Q000096:biosynthesis / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017118:Porphyria, Acute Intermittent / Q000235:genetics / Q000473:pathology*; D013548:Sweden; D016707:Tissue Fixation
D003062:Codon; D004279:DNA, Viral; D005404:Fixatives; D005557:Formaldehyde; D006418:Heme; D006147:Guanine; D011163:Hydroxymethylbilane Synthase; D000225:Adenine