Abstract
Hepatoblastoma (HBL), the most common childhood liver cancer is cured with surgical resection after chemotherapy or with liver transplantation if local invasion and multifocality preclude resection. However, variable survival rates of 60–80% and debilitating chemotherapy sequelae argue for more informed treatment selection, which is not possible by grading the Wnt-β-catenin over activity present in most HBL tumors. A hypothesis-generating whole transcriptome analysis shows that HBL tumors removed at transplantation are enriched most for cancer signaling pathways which depend predominantly on epidermal growth factor (EGF) signaling, and to a lesser extent, on aberrant Wnt-β-catenin signaling. We therefore evaluated whether EGFR, ASAP1, ERBB2 and ERBB4, which signal downstream after ligation of EGF, and which show aberrant expression in several other invasive cancers, would also predict HBL tumor invasiveness. Immunohistochemistry of HBL tumors (n = 60), which are histologically heterogeneous, shows that compared with well-differentiated fetal cells, less differentiated embryonal and undifferentiated small cells (SCU) progressively lose EGFR and ASAP1 expression. This trend is exaggerated in unresectable, locally invasive or metastatic tumors, in which embryonal tumor cells are EGFR-negative, while SCU cells are EGFR-negative and ASAP1-negative. Loss of EGFR-ASAP1 signaling characterizes undifferentiated and invasive HBL. EGFR-expressing HBL tumors present novel therapeutic targeting opportunities.
Highlights
Rare, hepatoblastoma (HBL) is the most common liver cancer during childhood, and accounts for nearly a tenth of all pediatric liver transplants in the United States[1,2]
Children with HBL included 23 who received liver transplantation for unresectable tumors, 40 in whom the tumor was removed with surgical resection, and one who only received diagnostic biopsy
We found that epidermal growth factor (EGF)/ERBB signaling genes made up a larger proportion of cancer signaling genes in GBM and Her[2] breast cancer signaling pathways, compared with those in the Wnt-β-catenin signaling pathway (Supplementary Table S3). qRT-PCR confirmed changes in gene expression for selected genes in the EGF/ERBB (EGFR, PI3C2G, MYC, PLCG1) and Wnt (Wnt2A, AXIN2, SRC) signaling pathways (Supplementary Table S4)
Summary
Hepatoblastoma (HBL) is the most common liver cancer during childhood, and accounts for nearly a tenth of all pediatric liver transplants in the United States[1,2] This public health impact can be alleviated if chemotherapy and surgical options are targeted to tumor biology. Potential second hits include several tumor-associated markers and mechanisms such as the Yes-associated protein 1 (Yap1), c-Myc, hepatocyte growth factor (HGF)/c-Met, NOTCH, MAP kinase, cyclin D, ki-67, telomerase reverse transcriptase (TERT), and RASS1FIA methylation status[13,14,15,16,17,18,19,20] This list may be incomplete because copy number gains are seen in several chromosomes in the tumor exome of surgically resected HBL21–23. Because resectable tumors outnumber those requiring transplantation four-fold, immunostaining studies were performed in samples from an expanded cohort of affected children treated with and without liver transplantation[6]
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