General paucity of genomic alteration and low tumor mutation burden in refractory and metastatic hepatoblastoma: comprehensive genomic profiling study

Lee, Hwajeong; Jabbour, Tony El; Ainechi, Sanaz; Elvin, Julia A.; Vergilio, Jo‐Anne; Suh, James; Ramkissoon, Shakti; Ali, Siraj M.; Schrock, Alexa B.; Fabrizio, David; Frampton, Garrett M.; Miller, Vincent A.; Stephens, Philip J.; Ross, Jeffrey S.

doi:10.1016/j.humpath.2017.10.007

Cited by 21 publications

(19 citation statements)

References 33 publications

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“…The tumor landscape may reveal novel druggable mutations, novel pathways for alternative chemotherapy, or changes in tumor clonality after primary chemotherapy that may help select more effective second line agents [83]. Unbiased tumor exome sequencing suggests that like many pediatric embryonal tumors, HB tumors harbor fewer mutations than tumors which affect adults [84]. Higher tumor mutation burden (TMB) renders tumors susceptible to immune therapy [85].…”

Section: Genomic Landscape and Tumor Targetingmentioning

confidence: 99%

Liver Transplantation for Pediatric Liver Cancer

Sindhi

Rohan

Tadros

et al. 2020

Cancers

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Unresectable hepatocellular carcinoma (HCC) was first removed successfully with total hepatectomy and liver transplantation (LT) in a child over five decades ago. Since then, children with unresectable liver cancer have benefitted greatly from LT and a confluence of several equally important endeavors. Regional and trans-continental collaborations have accelerated the development and standardization of chemotherapy regimens, which provide disease control to enable LT, and also serve as a test of unresectability. In the process, tumor histology, imaging protocols, and tumor staging have also matured to better assess response and LT candidacy. Significant trends include a steady increase in the incidence of and use of LT for hepatoblastoma, and a significant improvement in survival after LT for HCC with each decade. Although LT is curative for most unresectable primary liver sarcomas, such as embryonal sarcoma, the malignant rhabdoid tumor appears relapse-prone despite chemotherapy and LT. Pediatric liver tumors remain rare, and diagnostic uncertainty in some settings can potentially delay treatment or lead to the selection of less effective chemotherapy. We review the current knowledge relevant to diagnosis, LT candidacy, and post-transplant outcomes for these tumors, emphasizing recent observations made from large registries or larger series.

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Section: Genomic Landscape and Tumor Targetingmentioning

confidence: 99%

Liver Transplantation for Pediatric Liver Cancer

Sindhi

Rohan

Tadros

et al. 2020

Cancers

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“…While overall survival for children with HBL has improved over the years through cisplatin-based chemotherapy and subsequent resection, a substantial number of patients experience metastasis or are faced with aggressive tumors that are unresectable and do not respond favorably to chemotherapy 2–4 . Several recent studies reported that HBL is a genetically simple tumor with an average of 2.9 mutations per tumor predominately in β-catenin and NFE2L2 genes 5–7 and in the Wnt pathway 8 . These reports demonstrate that genomic mutations are only one part of the complex alterations observed in HBL.…”

Section: Introductionmentioning

confidence: 99%

PARP1 activation increases expression of modified tumor suppressors and pathways underlying development of aggressive hepatoblastoma

et al. 2018

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Hepatoblastoma (HBL) is a pediatric liver cancer that affects children under the age of three. Reduction of tumor suppressor proteins (TSPs) is commonly seen in liver cancer. However, in our studies we find that aggressive, chemo-resistant HBLs exhibit an elevation of TSPs. HBL patients with a classic phenotype have reduced TSP levels, but patients with aggressive HBL express elevated TSPs that undergo posttranslational modifications, eliminating their tumor suppression activities. Here we identify unique aggressive liver cancer domains (ALCDs) that are activated in aggressive HBL by PARP1-mediated chromatin remodeling leading to elevation of modified TSPs and activation of additional cancer pathways: WNT signaling and β-catenin. Inhibition of PARP1 blocks activation of ALCDs and normalizes expression of corresponding genes, therefore reducing cell proliferation. Our studies reveal PARP1 activation as a mechanism for the development of aggressive HBL, further suggesting FDA-approved PARP1 inhibitors might be used for treatment of patients with aggressive HBL.

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“…Indeed, it is postulated that the increase in mutation of β-catenin gene on exon 3, i.e. CTNNB1 is responsible for increase in translocation of β-catenin from the plasma membrane to cytoplasm and nucleus [25,26,78]. An increase in activation of Wnt/β-catenin signaling may also be secondary to activation of GPC3, NF-kB, GSK-3β, ERK1/2 and co-activator of β-catenin, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Later, scientists verified these initial findings and reported that somatic mutations in β-catenin gene are responsible for its accumulation inside the tumor cells, a crucial event in tumorigenesis [20,[24][25][26][27]. Indeed, it is proposed that hepatoblastoma presents with the highest rate (50-90%) of β-catenin mutations [4,28].…”

Section: Mutations In β-Catenin Gene Leads To Its Intracellular Accummentioning

confidence: 94%

Wnt/β-catenin signaling as a useful therapeutic target in hepatoblastoma

et al. 2019

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Hepatoblastoma is a malignant tumor in the liver of children that generally occurs at the age of 2–3 years. There have been ample evidence from the preclinical as well as clinical studies suggesting the activation of Wnt/β-catenin signaling in hepatoblastoma, which is mainly attributed to the somatic mutations in the exon 3 of β-catenin gene. There is increased translocation of β-catenin protein from the cell surface to cytoplasm and nucleus and intracellular accumulation is directly linked to the severity of the cancer. Accordingly, the alterations in β-catenin and its target genes may be used as markers in the diagnosis and prognosis of pediatric live tumors. Furthermore, scientists have reported the therapeutic usefulness of inhibition of Wnt/β-catenin signaling in hepatoblastoma and this inhibition of signaling has been done using different methods including short interfering RNA (siRNA), miRNA and pharmacological agents. Wnt/β-catenin works in association with other signaling pathways to induce the development of hepatoblastoma including Yes-associated protein (YAP)1 (YAP-1), mammalian target of rapamycin (mTOR) 1 (mTOR-1), SLC38A1, glypican 3 (GPC3), nuclear factor κ-light-chain-enhancer of activated B cells (NF-kB), epidermal growth factor receptor, ERK1/2, tumor necrosis factor-α (TNF-α), regenerating islet-derived 1 and 3 α (REG1A and 3A), substance P (SP)/neurokinin-1 receptor and PARP-1. The present review describes the key role of Wnt/β-catenin signaling in the development of hepatoblastoma. Moreover, the role of other signaling pathways in hepatoblastoma in association with Wnt/β-catenin has also been described.

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General paucity of genomic alteration and low tumor mutation burden in refractory and metastatic hepatoblastoma: comprehensive genomic profiling study

Cited by 21 publications

References 33 publications

Liver Transplantation for Pediatric Liver Cancer

Liver Transplantation for Pediatric Liver Cancer

PARP1 activation increases expression of modified tumor suppressors and pathways underlying development of aggressive hepatoblastoma

Wnt/β-catenin signaling as a useful therapeutic target in hepatoblastoma

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