Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations

• DOI: 10.1016/j.jhep.2014.07.003
• Publication Date: 2014-07-10T10:18:03Z
• Authors: Sílvia Vilarinho; E. Zeynep Erson-Omay; Akdes Serin Harmanci; Raffaella Morotti; Geneive Carrion-G...; Jacob Baranoski; A.S. Knisely; Udeme Ekong; Sukru Emre; Katsuhito Yasuno; Kaya Bilguvar; Murat Günel
• Keywords: 0303 health sciences; Carcinoma, Hepatocellular; Base Sequence; Sequence Homology, Amino Acid; NF-E2-Related Factor 2; Liver Neoplasms; Molecular Sequence Data; Mutation, Missense; Infant; Cholestasis, Intrahepatic; DNA, Neoplasm; 3. Good health; 03 medical and health sciences; Mutation; Humans; ATP-Binding Cassette Transporters; Female; Amino Acid Sequence; ATP Binding Cassette Transporter, Subfamily B, Member 11; Germ-Line Mutation; beta Catenin

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.