Characterization of pediatric hepatocellular carcinoma reveals genomic heterogeneity and diverse signaling pathway activation

• Published in: Pediatric blood & cancer Vol. 66; no. 7; pp. e27745 - n/a
• Main Authors: Haines, Katherine, Sarabia, Stephen F., Alvarez, Karla R., Tomlinson, Gail, Vasudevan, Sanjeev A., Heczey, Andras A., Roy, Angshumoy, Finegold, Milton J., Parsons, D. Williams, Plon, Sharon E., López‐Terrada, Dolores
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.07.2019
• Subjects: Activation; Adenomatous polyposis coli; Adolescent; Adult; Brain tumors; cancer; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Child; Child, Preschool; Children; Female; Genes; Hematology; Heparan sulfate proteoglycans; Hepatocellular carcinoma; Heterogeneity; Humans; Liver; Liver cancer; Liver diseases; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Male; MAP kinase; MAP Kinase Signaling System - genetics; MAPK/ERK; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oncology; p53 Protein; Pediatrics; Revisions; Signal transduction; Telomerase; TERT; Therapeutic applications; Tumors; Wnt protein; Wnt signaling; Wnt signaling; cancer; MAPK/ERK; TERT; liver
• ISSN: 1545-5009; 1545-5017
• DOI: 10.1002/pbc.27745

Background Pediatric hepatocellular carcinoma (HCC) is a rare liver tumor in children with a poor prognosis. Comprehensive molecular profiling to understand the underlying genomic drivers of this tumor has not been completed, and it is unclear whether nonfibrolamellar pediatric HCC is more genomically similar to hepatoblastoma or adult HCC. Procedure To characterize the molecular landscape of these tumors, we analyzed a cohort of 15 pediatric non‐FL‐HCCs by sequencing a panel of cancer‐associated genes and conducting copy‐number and gene‐expression analyses. Results We detected multiple types of molecular alterations in Wnt signaling genes, including APC inversion, AMER1 somatic mutation, and most commonly CTNNB1 intragenic deletions. There were multiple alterations to the telomerase pathway via TERT activation or ATRX mutation. Therapeutically targetable activating mutations in MAPK/ERK signaling pathway genes, including MAPK1 and BRAF, were detected in 20% of tumors. TP53 mutations occurred far less frequently in our pediatric HCC cohort than reported in adult cohorts. Tumors arising in children with underlying liver disease were found to be molecularly distinct from the remainder and lacking detectable oncogenic drivers, as compared with those arising in patients without a history of underlying liver disease; the majority of both types were positive for glypican‐3, another potential therapeutic target. Conclusion Our study revealed pediatric HCC to be a molecularly heterogeneous group of tumors. Those non‐FL‐HCC tumors arising in the absence of underlying liver disease harbor genetic alterations affecting multiple cancer pathways, most notably Wnt signaling, and share some characteristics with adult HCC.