Fibrolamellar hepatocellular carcinoma (FLC) is a disease that occurs in children and young adults. The development of FLC is associated with creation of a fusion oncoprotein DNAJB1-PKAc kinase, which activates multiple cancerassociated pathways. The aim of this study was to examine the role of human genomic regions, called cancer-enhancing genomic regions or aggressive liver cancer domains (CEGRs/ALCDs), in the development of FLC. Previous studies revealed that CEGRs/ALCDs are located in multiple oncogenes and cancer-associated genes, regularly silenced in normal tissues. Using the regulatory element locus intersection (RELI) algorithm, we searched a large
Glypican-3 (GPC3) is a cell-surface glycoprotein that is frequently overexpressed in hepatocellular carcinoma. GPC3 undergoes extensive post-translational modification including cleavage and glycosylation. This review focuses on the structure and function of GPC3 in liver cancer, highlighting the post-translation modification (PTM) of the tertiary and quaternary structures of GPC3 as a potential oncogenic regulatory mechanism. We propose that the function of GPC3 in normal development can vary with extensive PTM and that dysregulation of these processes leads to disease. Defining the regulatory impact of these modifications can provide a deeper understanding of the role of GPC3 in oncogenesis, epithelial-mesenchymal transition, and drug development. Through review of current literature, this paper provides a unique perspective on the role of GPC3 in liver cancer, focusing on potential regulatory mechanisms of post-translational modifications on GPC3 function at the molecular, cellular, and disease level.
Hepatoblastoma is the most common malignant liver tumor of childhood, with liver transplant and extended resection used as surgical treatments for locally advanced tumors. Although each approach has well-described post-operative complications, quality-of-life outcomes have not been described following the two interventions. Long-term pediatric survivors of hepatoblastoma who underwent conventional liver resection or liver transplantation at a single institution from January 2000–December 2013 were recruited to complete quality-of-life surveys. Survey responses for the Pediatric Quality of Life Generic Core 4.0 (PedsQL, n = 30 patient and n = 31 parent surveys) and Pediatric Quality of Life Cancer Module 3.0 (PedsQL-Cancer, n = 29 patient and n = 31 parent surveys) were collected from patients and parents. The mean total patient-reported PedsQL score was 73.7, and the parent-reported score was 73.9. There were no significant differences in scores on the PedsQL between patients who underwent resection compared to those who underwent transplantation (p > 0.05 for all comparisons). On the PedsQL-Cancer module, procedural anxiety scores were significantly lower for patients who underwent resection as compared to transplant (M = 33.47 points less, CI [−60.41, −6.53], p-value 0.017). This cross-sectional study demonstrates that quality of life outcomes are overall similar among patients receiving transplants and resections. Patients who received a resection reported worse procedural anxiety.
e22015 Background: Trisomy 18 (T18) is the second most common aneuploidy caused by additional copies of chromosome 18. It occurs at a rate of 1 in 2000-6000 live births, with current 1-year survival rates between 5-10% of live births. Meta-analysis of tumor in T18 patients revealed 67 tumors, with 44 (66%) being HB. The contribution of underlying genetic alterations to tumorigenesis is incompletely understood. There is a reversed gender ratio in children with T18 and HB as well as more favorable histology and response to treatment. These suggest an alternative molecular pathway in these cases might promote tumorigenesis. Although there is an association between trisomy 18 and hepatoblastoma, the cause of this increased incidence is unknown. We hypothesize that SMAD4/TGFβ signaling in conjunction with canonical Wnt signaling has a role in T18 HB tumor development as well as a more fetal tumor histology. Methods: Seven patients with T18 were treated at CCHMC for HB. Five patient samples were collected at time of surgery for evaluation. Patient samples and data were collected with informed consent and institutional IRB approval. We performed transcriptomic analysis using RNA bulk sequencing data for five paired background and tumor samples. Further gene and protein expression were evaluated and compared to non-syndromic patients with HB. Histologic evaluation for tumor subtype and target proteins was performed. Results: Of the seven patients evaluated, six (85.7%) were female with a median age of diagnosis of 9 months. All patients underwent hepatectomy, with final pathology demonstrating predominantly fetal histology. All patients are currently in remission. Bulk RNAseq demonstrated upregulation of SMAD4 and TGFβ, as well as upregulation of canonical Wnt signaling pathway including Wnt3 and transcription factors Lef1, TCF4, and APC in tumor of T18 patients compared to background and non-syndromic HB patients. β-catenin immunostaining demonstrates increased or stabilized expression in tumor compared to background liver consistent with non-syndromic HB. Conclusions: We have identified a novel tumorigenic mechanism of HB in T18. Upregulation of SMAD4 in T18 results in increased TGFβ signaling, with potential crosstalk between SMAD4/TGFβ and Wnt/β-catenin signaling promoting cancer development. Further evaluation is required to understand the pathway crosstalk and impact of genetic mutation on pathway regulation.
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