title: Spectrum of HNF1A somatic mutations in hepatocellular adenoma differs from that in patients with MODY3 and suggests genotoxic damage.
abstract: OBJECTIVE
  Maturity onset diabetes of the young type 3 (MODY3) is a consequence of heterozygous germline mutation in HNF1A. A subtype of hepatocellular adenoma (HCA) is also caused by biallelic somatic HNF1A mutations (H-HCA), and rare HCA may be related to MODY3. To better understand a relationship between the development of MODY3 and HCA, we compared both germline and somatic spectra of HNF1A mutations.
  
  
  METHODS
  We compared 151 somatic HNF1A mutations in HCA with 364 germline mutations described in MODY3. We searched for genotoxic and oxidative stress features in HCA and surrounding liver tissue.
  
  
  RESULTS
  A spectrum of HNF1A somatic mutations significantly differed from the germline changes in MODY3. In HCA, we identified a specific hot spot at codon 206, nonsense and frameshift mutations mainly in the NH(2)-terminal part, and almost all amino acid substitutions were restricted to the POU-H domain. The high frequency of G-to-T tranversions, predominantly found on the nontranscribed DNA strand, suggested a genotoxic mechanism. However, no features of oxidative stress were observed in the nontumor liver tissue. Finally, in a few MODY3 patients with HNF1A germline mutation leading to amino acid substitutions outside the POU-H domain, we identified a different subtype of HCA either with a gp130 and/or CTNNB1 activating mutation.
  
  
  CONCLUSIONS
  Germline HNF1A mutations could be associated with different molecular subtypes of HCA. H-HCA showed mutations profoundly inactivating hepatocyte nuclear factor-1alpha function; they are associated with a genotoxic signature suggesting a specific toxicant exposure that could be associated with genetic predisposition.
authors.affiliation: Institut National de Santé et de Recherche Médicale, U674, Génomique Fonctionnelle des Tumeurs Solides, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jeannot
authors.forename: Lucille
authors.initials: L
authors.lastname: Mellottee
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Jeanne
authors.initials: J
authors.lastname: Tran Van Nhieu
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bacq
authors.forename: Sophie
authors.initials: S
authors.lastname: Michalak
authors.forename: David
authors.initials: D
authors.lastname: Buob
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D018248:Adenoma, Liver Cell / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D004249:DNA Damage / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha
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