title: Loss of EGFR-ASAP1 signaling in metastatic and unresectable hepatoblastoma.
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.
authors.affiliation: Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Avenue, Department of Pathology, Pittsburgh, PA 15224, USA.
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
authors.affiliation: Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Avenue, Pediatric Abdominal Transplant Surgery, Pittsburgh, PA 15224, USA.
authors.forename: Mylarappa
authors.initials: M
authors.lastname: Ningappa
authors.affiliation: Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Avenue, Pediatric Abdominal Transplant Surgery, Pittsburgh, PA 15224, USA.
authors.forename: Chethan
authors.initials: C
authors.lastname: Ashokkumar
authors.affiliation: Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Avenue, Pediatric Abdominal Transplant Surgery, Pittsburgh, PA 15224, USA.
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.affiliation: Department of Bioengineering, University of California San Diego, LA Jolla, CA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Min
authors.affiliation: Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Avenue, Pediatric Abdominal Transplant Surgery, Pittsburgh, PA 15224, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Avenue, Department of Pathology, Pittsburgh, PA 15224, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Schmitt
authors.affiliation: Department of Bioengineering, University of California San Diego, LA Jolla, CA, USA.
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, 1216 E. Abramson's Research Center, 34th and Civic Center Blvd., ARC 1216E, Philadelphia, PA. 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Avenue, Pediatric Abdominal Transplant Surgery, Pittsburgh, PA 15224, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sindhi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000172:deficiency* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018197:Hepatoblastoma / Q000235:genetics* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D016031:Liver Transplantation; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D008297:Male; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D059467:Transcriptome; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D051176:beta Catenin; C117891:ASAP1 protein, human; C495270:CTNNB1 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human