title: Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations.
abstract: Hepatocellular carcinoma (HCC) rarely occurs in childhood. We describe a patient with new onset of pruritus at 8 months of age who at 17 months of age was found to have a 2.5 cm HCC. To delineate the possible genetic basis of this tumour, we performed whole exome sequencing (WES) of the germline DNA and identified two novel predictably deleterious missense mutations in ABCB11, encoding bile salt export pump (BSEP), confirmed in the parental DNA as bi-allelic and inherited. Although inherited ABCB11 mutations have previously been linked to HCC in a small number of cases, the molecular mechanisms of hepatocellular carcinogenesis in ABCB11 disease are unknown. WES of the HCC tissue uncovered somatic driver mutations in the beta-catenin (CTNNB1) and nuclear-factor-erythroid-2-related-factor-2 (NFE2L2) genes. Moreover, clonality analysis predicted that the CTNNB1 mutation was clonal and occurred earlier during carcinogenesis, whereas the NFE2L2 mutation was acquired later. Interestingly, background liver parenchyma showed no inflammation or fibrosis and BSEP expression was preserved. This is the first study to identify somatic CTNNB1 and NFE2L2 mutations in early childhood arisen in the setting of inherited bi-allelic ABCB11 mutations. Rapid WES analysis expedited this child's diagnosis and treatment, and likely improved her prognosis.
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, United States; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, United States.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Vilarinho
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, United States; Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, United States.
authors.forename: E Zeynep
authors.initials: EZ
authors.lastname: Erson-Omay
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, United States; Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, United States.
authors.forename: Akdes Serin
authors.initials: AS
authors.lastname: Harmanci
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06510, United States.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Morotti
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, United States; Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, United States.
authors.forename: Geneive
authors.initials: G
authors.lastname: Carrion-Grant
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, United States; Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, United States.
authors.forename: Jacob
authors.initials: J
authors.lastname: Baranoski
authors.affiliation: Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.affiliation: Department of Pediatrics, Section of Pediatric Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT 06510, United States.
authors.forename: Udeme
authors.initials: U
authors.lastname: Ekong
authors.affiliation: Department of Surgery, Section of Transplantation and Immunology, Yale School of Medicine, New Haven, CT 06510, United States.
authors.forename: Sukru
authors.initials: S
authors.lastname: Emre
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, United States; Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, United States.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Yasuno
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, United States; Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, United States.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, United States; Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, United States. Electronic address: murat.gunel@yale.edu.
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002780:Cholestasis, Intrahepatic / Q000150:complications / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D051176:beta Catenin / Q000235:genetics*
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C495270:CTNNB1 protein, human; D004273:DNA, Neoplasm; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051176:beta Catenin
keywords: ABCB11 mutations; CTNNB1; NFE2L2; Paediatric hepatocellular carcinoma; Whole exome sequencing