Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors

in Endocrine-Related Cancer
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  • 1 Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
  • 2 Department of Diabetology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
  • 3 Department of Gastroenterology and Digestive Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
  • 4 Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
  • 5 Department of Digestive Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
  • 6 Department of Gastroenterology, Robert-Debré Hospital, Reims, France
  • 7 Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Correspondence should be addressed to G Assié: guillaume.assie@aphp.fr
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Duodenopancreatic neuroendocrine tumors (DPNETs) aggressiveness is heterogeneous. Tumor grade and extension are commonly used for prognostic determination. Yet, grade classes are empirically defined, with regular updates changing the definition of classes. Genomic screening may provide more objective classes and reflect tumor biology. The aim of this study was to provide a transcriptome classification of DPNETs. We included 66 DPNETs, covering the entire clinical spectrum of the disease in terms of secretion, grade, and stage. Three distinct molecular groups were identified, associated with distinct outcomes (log-rank P < 0.01): (i) better-outcome DPNETs with pancreatic beta-cell signature. This group was mainly composed of well-differentiated, grade 1 insulinomas; (ii) poor-outcome DPNETs with pancreatic alpha-cell and hepatic signature. This group included all neuroendocrine carcinomas and grade 3 DPNETs, but also some grade 1 and grade 2 DPNETs and (iii) intermediate-outcome DPNETs with pancreatic exocrine and progenitor signature. This group included grade 1 and grade 2 DPNETs, with some insulinomas. Fibrinogen gene FGA expression was one of the topmost expressed liver genes. FGA expression was associated with disease-free survival (HR = 1.13, P = 0.005) and could be validated on two independent cohorts. This original pathophysiologic insight provides new prognostic classification perspectives.

Supplementary Materials

    • Supplementary Figure 1: correlation between ISMARA predicted activity and mRNA expression for HNF1A (A) and HNF4A (B). C: Tissue of origin of the top overexpressed genes for the three transcriptome groups of DPNETs.
    • Supplementary Figure 2: Liver genes expression in the three DPNETS groups. Tumor location is provided (Pancreas, Liver, and Lymph Node).
    • Supplementary Table 1: individual clinical characteristics for the Chan et al. cohort. Comparison with the Cochin cohort is providing.
    • Supplementary Table 2: gene list for each pancreatic cell subtype gene set.
    • Supplementary Table 3: RLE normalized expression of 9,800 most variable genes.
    • Supplementary Table 4: individual clinical characteristics.
    • Supplementary Table 5: Gene Set Enrichment analysis of DPNET groups using signatures of mature pancreatic cells.
    • Supplementary Table 6: Gene Set Enrichment analysis of DPNET groups using signatures of fetal and progenitor pancreatic cells.
    • Supplementary Table 7: detailed oPOSSUM analysis of poor-outcome DPNETs signature.
    • Supplementary Table 8: The top 100 genes of each group is provided. For each gene, the tissue with the highest expression is provided (source: the Human Protein Atlas).
    • Supplementary Table 9: mean gene expression in three DPNET groups with p-values.

 

Society for Endocrinology

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