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- Title
Spectrum of HNF1A Somatic Mutations in Hepatocellular Adenoma Differs From That in Patients With MODY3 and Suggests Genotoxic Damage.
- Authors
Jeannot, Emmanuelle; Mellottee, Lucille; Bioulac-Sage, Paulette; Balabaud, Charles; Scoazec, Jean-Yves; Van Nhieu, Jeanne Tran; Bacq, Yannick; Michalak, Sophie; Buob, David; Laurent-Puig, Pierre; Rusyn, Ivan; Zucman-Rossi, Jessica
- 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[sub 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 gpl30 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-1α function; they are associated with a genotoxic signature suggesting a specific toxicant exposure that could be associated with genetic predisposition. Diabetes 59:1836-1844, 2010
- Subjects
LIVER cancer; ADENOMA; GENETIC toxicology; DIABETES; TYPE 2 diabetes
- Publication
Diabetes, 2010, Vol 59, Issue 7, p1836
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db09-1819