Supplementary Tables S1-S13. Supplementary Table S1. Clinical information and the summary of experiments performed on each sample. Supplementary Table S2. List of genes and regions captured for targeted deep sequencing. Supplementary Table S3. dbSNP ID list for which target baits were designed. Supplementary Table S4. Non-silent mutations detected in a validation cohort by targeted deep sequencing. Supplementary Table S5. Validated non-silent somatic mutations by PCR-based deep sequencing. Supplementary Table S6. Validated silent/non-silent somatic mutations used for clonal analysis of multiple samples from PBL001. Supplementary Table S7. Significantly hypo-/hyper-methylated gene sets in PBL compared to normal pancreas. Supplementary Table S8. Fusion genes detected by whole transcriptome sequencing in PBL. Supplementary Table S9. Genes with a significant differential expression between PBL and normal pancreatic samples. Supplementary Table S10. Significant gene set enrichment in comparison between PBL and normal pancreas. Supplementary Table S11. List of differentially expressed genes in each gene cluster identified by hierarchical clustering. Supplementary Table S12. Top 20 significantly enriched pathways in each gene cluster. Supplementary Table S13. Gene coefficients of PC1 and PC2.
Funding
University of Tokyo
KAKENHI
Japan Society for the Promotion of Science
Research on Measures for Intractable Diseases, Health and Labor Sciences
Ministry of Health, Labour and Welfare
Research on Health Sciences focusing on Drug Innovation
Japan Health Sciences Foundation
Core Research for Evolutional Science and Technology
Japan Science and Technology Agency
AMED
Pancreas Research Foundation of Japan
ARTICLE 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.
