Figure 1. (IMAGE)

Osaka University

Figure 1.

Caption

Genomic alterations in gastrointestinal system neuroendocrine carcinomas (GIS-NECs). Landscape of genomic alterations in samples from patients with GIS-NEC. The left oncoplot shows whole-genome sequencing (WGS) data and representative gene expression data obtained from frozen samples. The cases are arranged from left to right in descending order of the number of structural variants in each primary organ. Asterisks, organoid samples. The right oncoplot shows whole-exome sequencing data from a different subset of patients than those for whom WGS data were available. H&E staining and synaptophysin immunolabeling of TP53 and RB1 double knockout (TR-KO) organoids before and after Notch signaling was blocked with a γ-secretase inhibitor (DAPT). The number of synaptophysin-positive cells was increased by treatment with the Notch inhibitor. Scale bar, 100 µM. Unsupervised hierarchical cluster analysis using 2,000 high variant probes for DNA methylation in GIS-NECs. Integration of RNA-seq and DNA methylation array data comparing GIS-NECs with normal tissues. RNA-seq data were filtered using significant differentially expressed genes (DEGs) (abs [log2FC]) ≥ 1 with significant false discovery rate values (< 0.05). DNA methylation assay data were filtered using differentially methylated regions (DMR) (abs [△β value] ≥ 0.1) with significant adjPvals (< 0.05). The area of the figure showing high gene expression level and hypermethylation contains 199 DMRs, of which 39 (19.6%) are transcription factors (TFs, red dots), including SOX2 and ASCL1. In contrast, the area of the figure showing high gene expression level and hypomethylation contains 424 DMRs, of which 28 (6.6%) are TFs. CHGA, chromogranin A. Schematic of NET-AKR fusion genes detected in two gastric NECs. The neuroepithelioma transforming 1 (NET1) gene is a specific guanine nucleotide exchange factor for RhoA. Both aldo-keto reductase family 1 members C3 (AKR1C3) and C4 (AKR1C4) are reductase enzymes that play critical roles in the biotransformation of endogenous substrates such as steroids. The chimeric genes demonstrate in-frame fusion of the NET1 amino terminus (exons 1–3) and the AKR1C3 carboxyl terminus (exons 2–9) or the AKR1C4 carboxyl terminus (exons 6–9). NLS, nuclear localization signal; DH, Dbl homology; PH, pleckstrin homology; PDZ, post-synaptic density 95; aa, amino acids. Gastric NEC with the Merkel cell polyomavirus (MCPyV) [Case NE002]. The read depth along the polyomavirus genome is shown in blue, and read pairs bridging the polyomavirus genome and the integration site on chromosome 8 are indicated by red lines. Polyomavirus genes are indicated by Large T Antigen, Small T Antigen, VP1, VP2, and VP3.

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©2021 Shinichi Yachida et al., Cancer Discovery

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