Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1␣ (HNF1␣) and ␤-catenin were sequenced. No tumors were mutated in both HNF1␣ and ␤-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1␣ mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10 ؊4 ), lack of cytological abnormalities (P < 10 ؊6 ), and no inflammatory infiltrates (P < 10 ؊4 ). In contrast, the group of tumors defined by ␤-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10 ؊5 ). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P ‫؍‬ 10 ؊3 ), ductular reaction (P < 10 ؊2 ), and dystrophic vessels (P ‫؍‬ .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the ␤-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1␣ mutated tumors (P ‫؍‬ .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with ␤-catenin activation have a higher risk of malignant transformation. (

ABSTRACT:Cytochrome P450 (P450) enzymes and ATP-binding cassette (ABC) transporters modulate the transport and metabolism of both endogenous and exogenous substrates and could play crucial roles in the human brain. In this study, we report the transcript expression profile of seven ABC transporters (ABCB1, ABCC1-C5, and ABCG2), 24 P450s (CYP1, CYP2, and CYP3 families and CYP46A1), and 14 related transcription factors [aryl hydrocarbon receptor, nuclear receptor (NR)1I2/pregnane X receptor, NR1I3/constitutive androstane receptor and NR1C/peroxisome proliferator-activated receptor, NR1H/liver X receptor, NR2B/retinoid X receptor, and NR3A/estrogen receptor subfamilies] in the whole brain, the dura mater, and 17 different encephalic areas. In addition, Western blotting and immunohistochemistry analysis were used to characterize the distribution of the P450s at the cellular and subcellular levels in some brain regions. Our results show the presence of a large variety of xenobiotic transporters and metabolizing enzymes in human brain and show for the first time their apparent selective distribution in different cerebral regions. The most abundant transporters were ABCC5 and ABCG2, which, interestingly, had a higher mRNA expression in the brain compared with that found in the liver. CYP46A1, CYP2J2, CYP2U1, CYP1B1, CYP2E1, and CYP2D6 represented more than 90% of the total P450 and showed selective distribution in different brain regions. Their presence in both microsomal and mitochondrial fractions was shown both in neuronal and glial cells in several brain areas. Thus, our study shows key enzymes of cholesterol and fatty acid metabolism to be present in the human brain and provides novel information of importance for elucidation of enzymes responsible for normal and pathological processes in the human brain.The cytochrome P450 (P450) enzymes belonging to families 1 through 3 and many ATP-binding cassette (ABC) transporters are primarily known for their role in xenobiotic transport and metabolism. These proteins exert their activity mainly in the liver but have also been found in other tissues such as lung, kidney, intestine, placenta, and brain. The extrahepatic localization of these proteins suggests important and unrecognized activities toward endogenous substrates. We hypothesize that the roles of these proteins in transport and metabolism both of endogenous and endogenous compounds are important in the human brain, but at present there is a significant lack of knowledge regarding the distribution of P450s and ABC transporters throughout the human brain.This work was supported by a grant from Servier Technology. Article, publication date, and citation information can be found at

OBJECTIVEMaturity 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 METHODSWe 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.RESULTSA 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 NH2-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.CONCLUSIONSGermline 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.