Spectrum of HNF1A somatic mutations in hepatocellular adenoma differs from that in patients with MODY3 and suggests genotoxic damage. Academic Article uri icon

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. RESEARCH DESIGN AND 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.

published proceedings

  • Diabetes

author list (cited authors)

  • Jeannot, E., Mellottee, L., Bioulac-Sage, P., Balabaud, C., Scoazec, J., Tran Van Nhieu, J., ... Zucman-Rossi, J.

citation count

  • 48

complete list of authors

  • Jeannot, Emmanuelle||Mellottee, Lucille||Bioulac-Sage, Paulette||Balabaud, Charles||Scoazec, Jean-Yves||Tran Van Nhieu, Jeanne||Bacq, Yannick||Michalak, Sophie||Buob, David||Laurent-Puig, Pierre||Rusyn, Ivan||Zucman-Rossi, Jessica

publication date

  • July 2010