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Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma
- Source :
- Cancer research. 78(4)
- Publication Year :
- 2017
-
Abstract
- Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment. Significance: Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting. Cancer Res; 78(4); 865–76. ©2017 AACR.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Gene Expression Profiling
Wnt signaling pathway
Pancreatoblastoma
LGR5
Biology
medicine.disease
Pediatric cancer
Loss of heterozygosity
Transcriptome
Pancreatic Neoplasms
03 medical and health sciences
030104 developmental biology
medicine.anatomical_structure
Oncology
medicine
Cancer research
Humans
Exome
Female
Allele
Pancreas
Child
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 78
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....61a83bb232a1c95f78c74a28912c43d1