title: Association of CYP1B1 germ line mutations with hepatocyte nuclear factor 1alpha-mutated hepatocellular adenoma.
abstract: Biallelic somatic mutations of TCF1 coding for hepatocyte nuclear factor 1alpha (HNF1alpha) are found in 50% of the hepatocellular adenoma (HCA) cases usually associated with oral contraception. In rare cases, HNF1alpha germ line mutations could also predispose to familial adenomatosis. In order to identify new genetic factors predisposing to HNF1alpha-mutated HCA, we searched for mutations in genes involved in the metabolism of estrogen. For 10 genes (CYP1A1, CYP1A2, CYP3A4, CYP3A5, COMT, UGT2B7, NQO1, GSTM1, GSTP1, and GSTT1), we did not find mutations nor differences in the allele distribution among 32 women presenting HNF1alpha-mutated adenomas compared with 58 controls. In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1alpha-mutated adenomas compared with none in 58 controls. We confirmed these results with the identification of four additional CYP1B1 mutations in a second series of 26 cases. No mutations were found in the control group, which was extended to 98 individuals, and only a known rare genetic variant was observed in two controls (P = 0.0003). We did an ethoxyresorufin O-deethylase assay to evaluate the functional consequence of the CYP1B1 mutations. We found reduced enzymatic activity in each CYP1B1 variant. In addition, an E229K CYP1B1 mutation was found in a woman with a germ line HNF1alpha mutation in a familial adenomatosis context. In this large family, all three patients with adenomatosis bore both HNF1 and CYP1B1 germ line mutations. In conclusion, our data suggested that CYP1B1 germ line-inactivating mutations might increase the incidence of HCA in women with HNF1alpha mutations.
authors.affiliation: INSERM, U674, Génomique Fonctionnelle des Tumeurs Solides, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jeannot
authors.forename: Karine
authors.initials: K
authors.lastname: Poussin
authors.forename: Laurence
authors.initials: L
authors.lastname: Chiche
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bacq
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sturm
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Catherine
authors.initials: C
authors.lastname: Buffet
authors.forename: Jeanne Tran
authors.initials: JT
authors.lastname: Van Nhieu
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Claudia
authors.initials: C
authors.lastname: de Toma
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D018248:Adenoma, Liver Cell / Q000201:enzymology / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases; D002648:Child; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics*; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D010375:Pedigree
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1