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Association of CYP1B1 Germ Line Mutations with Hepatocyte Nuclear Factor 1–Mutated Hepatocellular Adenoma

¹ Inserm, U674, Génomique Fonctionnelle des Tumeurs Solides; ² Université Paris 7, Denis Diderot, Institut Universitaire d'Hématologie, Centre d'Etude du Polymorphisme Humain; ³ Service de Cytogénétique AP-HP, Saint Antoine, Université Pierre et Marie Curie; ⁴ Inserm, U775, Université Paris 5, Paris, France; ⁵ CHU Caen, Service de Chirurgie, Caen Cedex, France; ⁶ Hôpital Trousseau, Service d'Hépatogastroentérologie, Tours, France; ⁷ CHU Albert Michallon, Laboratoire de Pathologie Cellulaire, Grenoble, France; ⁸ Hôpital Edouard Herriot, Service d'Anatomopathologie, Lyon, France; ⁹ AP-HP, CHU de Bicêtre, Service d'Hépatologie, Le Kremlin-Bicêtre, France; ¹⁰ AP-HP, Hôpital Henri-Mondor, Service d'Anatomopathologie, Créteil, France; and ¹¹ Inserm, U889, Université Bordeaux 2, IFR66, CHU Bordeaux, Hôpital Pellegrin, Bordeaux, France

Requests for reprints: Jessica Zucman-Rossi, INSERM U674, 27 rue Juliette Dodu, 75010 Paris, France. Phone: 33-1537-25166; Fax: 33-1537-25158; E-mail: zucman{at}cephb.fr.

Biallelic somatic mutations of TCF1 coding for hepatocyte nuclear factor 1 (HNF1) are found in 50% of the hepatocellular adenoma (HCA) cases usually associated with oral contraception. In rare cases, HNF1 germ line mutations could also predispose to familial adenomatosis. In order to identify new genetic factors predisposing to HNF1-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 HNF1-mutated adenomas compared with 58 controls. In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1-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 HNF1 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 HNF1 mutations. [Cancer Res 2007;67(6):2611–6]

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