Hepatocellular carcinoma associated with tight‐junction protein 2 deficiency

Zhou, Shengmei; Hertel, Paula M.; Finegold, Milton J.; Wang, Larry; Kerkar, Nanda; Wang, Jing; Wong, Lee‐Jun C.; Plon, Sharon E.; Sambrotta, Melissa; Foskett, Pierre; Niu, Zhiyv; Rj, Thompson; Knisely, A. S.

doi:10.1002/hep.27872

Cited by 73 publications

(48 citation statements)

References 5 publications

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“…Consistent with our results, analysis of pediatric HCC in patients with progressive familial intrahepatic cholestasis type 2 (PFIC2), caused by ABCB11 mutation, by exome sequencing also yielded no pathogenic somatic mutations and only widespread copy‐number gain . Tumor WES from a single patient in our study with familial hypercholanemia (germline TJP2 mutations) found no oncogenic driver mutations and only a single VUS in the SET gene . The Pediatric Solid Tumor mutation panel utilized in this study contains the genes most commonly mutated in adult HCC.…”

Section: Discussionsupporting

confidence: 87%

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

Haines

Sarabia

Alvarez

et al. 2019

Pediatric Blood & Cancer

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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.

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Section: Discussionsupporting

confidence: 87%

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

Haines

Sarabia

Alvarez

et al. 2019

Pediatric Blood & Cancer

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“…This case (in addition to another concurrent finding at another institution) was the first report of an association of TJP2 deficiency and HCC. 22 Finally, 1 patient with previously unexplained proteinuria was found to carry an X-linked CLCN5 mutation. Parental samples were available for testing in 13 of these 15 diagnostic cases.…”

Section: Resultsmentioning

confidence: 99%

Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors

et al. 2016

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IMPORTANCE Whole-exome sequencing (WES) has the potential to reveal tumor and germline mutations of clinical relevance, but the diagnostic yield for pediatric patients with solid tumors is unknown. OBJECTIVE To characterize the diagnostic yield of combined tumor and germline WES for children with solid tumors. DESIGN Unselected children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumors were prospectively enrolled in the BASIC3 study at a large academic children’s hospital during a 23-month period from August 2012 through June 2014. Blood and tumor samples underwent WES in a certified clinical laboratory with genetic results categorized on the basis of perceived clinical relevance and entered in the electronic health record. MAIN OUTCOMES AND MEASURES Clinical categorization of somatic mutations; frequencies of deleterious germline mutations related to patient phenotype and incidental medically-actionable mutations. RESULTS Of the first 150 participants (80 boys and 70 girls, mean age, 7.4 years), tumor samples adequate for WES were available from 121 patients (81%). Somatic mutations of established clinical utility (category I) were reported in 4 (3%) of 121 patients, with mutations of potential utility (category II) detected in an additional 29 (24%) of 121 patients. CTNNB1 was the gene most frequently mutated, with recurrent mutations in KIT, TSC2, and MAPK pathway genes (BRAF, KRAS, and NRAS) also identified. Mutations in consensus cancer genes (category III) were found in an additional 24 (20%) of 121 tumors. Fewer than half of somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype were discovered in 15 (10%) of 150 cases: 13 pathogenic or likely pathogenic dominant mutations in adult and pediatric cancer susceptibility genes (including 2 each in TP53, VHL, and BRCA1), 1 recessive liver disorder with hepatocellular carcinoma (TJP2), and 1 renal diagnosis (CLCN5). Incidental findings were reported in 8 (5%) of 150 patients. Most patients harbored germline uncertain variants in cancer genes (98%), pharmacogenetic variants (89%), and recessive carrier mutations (85%). CONCLUSIONS AND RELEVANCE Tumor and germline WES revealed mutations in a broad spectrum of genes previously implicated in both adult and pediatric cancers. Combined reporting of tumor and germline WES identified diagnostic and/or potentially actionable findings in nearly 40% of newly diagnosed pediatric patients with solid tumors.

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“…In some patients, biallelic TJP2 mutation results in anicteric failure to thrive with pruritus and deficiency of fat‐soluble vitamins, or is clinically nonpenetrant (Carlton et al, ). In others, it leads to severe icterus with cholestatic hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma (Ge, Zhang, Xiao, Wang, & Zhang, ; Sambrotta et al, ; Vij, Shanmugam, Reddy, Sankaranarayanan, & Rela, ; Zhou et al, ). We have reviewed our seven unrelated patients in whom jaundice was associated with two TJP2 variants in trans (all compound heterozygotes), comparing their clinical presentations and courses, correlating these with types of variants, and analyzing molecular effects of three missense variants and one noncanonical splicing variant.…”

Section: Introductionmentioning

confidence: 99%

TJP2 hepatobiliary disorders: Novel variants and clinical diversity

et al. 2019

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To assess the spectrum of pediatric clinical phenotypes in TJP2 disease, we reviewed records of our seven patients in whom intrahepatic cholestasis was associated with biallelic TJP2 variants (13; 12 novel) and correlated clinical manifestations with mutation type. The effect of a splicing variant was analyzed with a minigene assay. The effects of three missense variants were analyzed with protein expression in vitro. Our patients had both remitting and persistent cholestasis. Three exhibited growth retardation. Six responded to treatment with cholestyramine, ursodeoxycholic acid, or both. Two had cholecystolithiasis. None required liver transplantation or developed hepatocellular or cholangiocellular malignancy. None manifested extrahepatic disease not attributable to effects of cholestasis. The variant c.2180-5T>G resulted in exon 15 skipping with in-frame deletion of 32 amino acid residues in TJP2. The three missense variants decreased but did not abolish TJP2 expression. Patients with truncating or canonical splice-site variants had clinically more severe disease. TJP2 disease in children includes a full clinical spectrum of severity, with mild or intermittent forms as well as the severe and minimal forms hitherto described. Biallelic TJP2 variants must be considered in children with clinically intermittent or resolved intrahepatic cholestasis.

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Hepatocellular carcinoma associated with tight‐junction protein 2 deficiency

Cited by 73 publications

References 5 publications

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

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

Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors

TJP2 hepatobiliary disorders: Novel variants and clinical diversity

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