Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors

in Endocrine-Related Cancer
Authors:
Marc Diedisheim Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Diabetology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Marc Diedisheim in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0002-0418-1107
,
Solène Dermine Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Gastroenterology and Digestive Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Solène Dermine in
Current site
Google Scholar
PubMed
Close
,
Anne Jouinot Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Anne Jouinot in
Current site
Google Scholar
PubMed
Close
,
Amandine Septier Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France

Search for other papers by Amandine Septier in
Current site
Google Scholar
PubMed
Close
,
Sébastien Gaujoux Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Digestive Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Sébastien Gaujoux in
Current site
Google Scholar
PubMed
Close
,
Bertrand Dousset Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Digestive Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Bertrand Dousset in
Current site
Google Scholar
PubMed
Close
,
Guillaume Cadiot Department of Gastroenterology, Robert-Debré Hospital, Reims, France

Search for other papers by Guillaume Cadiot in
Current site
Google Scholar
PubMed
Close
,
Etienne Larger Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Diabetology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Etienne Larger in
Current site
Google Scholar
PubMed
Close
,
Jérôme Bertherat Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Jérôme Bertherat in
Current site
Google Scholar
PubMed
Close
,
Raphael Scharfmann Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France

Search for other papers by Raphael Scharfmann in
Current site
Google Scholar
PubMed
Close
,
Benoit Terris Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Benoit Terris in
Current site
Google Scholar
PubMed
Close
,
Romain Coriat Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Gastroenterology and Digestive Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Romain Coriat in
Current site
Google Scholar
PubMed
Close
, and
Guillaume Assié Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Guillaume Assié in
Current site
Google Scholar
PubMed
Close

Correspondence should be addressed to G Assié: guillaume.assie@aphp.fr
Restricted access
Rent on DeepDyve

Sign up for journal news

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.

 

  • Collapse
  • Expand
  • Alcala N, Leblay N, Gabriel AAG, Mangiante L, Hervas D, Giffon T, Sertier AS, Ferrari A, Derks J & Ghantous A et al.2019 Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nature Communications 10 3407. (https://doi.org/10.1038/s41467-019-11276-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Balwierz PJ, Pachkov M, Arnold P, Gruber AJ, Zavolan M & Van Nimwegen E 2014 ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs. Genome Research 24 869884. (https://doi.org/10.1101/gr.169508.113)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Blodgett DM, Nowosielska A, Afik S, Pechhold S, Cura AJ, Kennedy NJ, Kim S, Kucukural A, Davis RJ & Kent SC et al.2015 Novel observations from next-generation RNA sequencing of highly purified human adult and fetal islet cell subsets. Diabetes 64 31723181. (https://doi.org/10.2337/db15-0039)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bramswig NC, Everett LJ, Schug J, Dorrell C, Liu C, Luo Y, Streeter PR, Naji A, Grompe M & Kaestner KH 2013 Epigenomic plasticity enables human pancreatic α to β cell reprogramming. Journal of Clinical Investigation 123 12751284. (https://doi.org/10.1172/JCI66514)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cancer Genome Atlas Research Network, Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C & Stuart JM 2013 The cancer genome atlas pan-cancer analysis project. Nature Genetics 45 11131120. (https://doi.org/10.1038/ng.2764)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cejas P, Drier Y, Dreijerink KMA, Brosens LAA, Deshpande V, Epstein CB, Conemans EB, Morsink FHM, Graham MK & Valk GD et al.2019 Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. Nature Medicine 25 12601265. (https://doi.org/10.1038/s41591-019-0493-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chan CS, Laddha SV, Lewis PW, Koletsky MS, Robzyk K, Da Silva E, Torres PJ, Untch BR, Li J & Bose P et al.2018 ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup. Nature Communications 9 4158. (https://doi.org/10.1038/s41467-018-06498-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Conesa A, Madrigal P, Tarazona S, Gomez-Cabrero D, Cervera A, McPherson A, Szcześniak MW, Gaffney DJ, Elo LL & Zhang X et al.2016 A survey of best practices for RNA-seq data analysis. Genome Biology 17 13. (https://doi.org/10.1186/s13059-016-0881-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M & Gingeras TR 2013 STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29 1521. (https://doi.org/10.1093/bioinformatics/bts635)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Duan S, Gong B, Wang P, Huang H, Luo L & Liu F 2018 Novel prognostic biomarkers of gastric cancer based on gene expression microarray: COL12A1, GSTA3, FGA and FGG. Molecular Medicine Reports 18 37273736. (https://doi.org/10.3892/mmr.2018.9368)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gaujoux R & Seoighe C 2010 A flexible R package for nonnegative matrix factorization. BMC Bioinformatics 11 367. (https://doi.org/10.1186/1471-2105-11-367)

  • Han Y, Gao S, Muegge K, Zhang W & Zhou B 2015 Advanced applications of RNA sequencing and challenges. Bioinformatics and Biology Insights 9 2946. (https://doi.org/10.4137/BBI.S28991)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ho Sui SJ, Mortimer JR, Arenillas DJ, Brumm J, Walsh CJ, Kennedy BP & Wasserman WW 2005 oPOSSUM: identification of over-represented transcription factor binding sites in co-expressed genes. Nucleic Acids Research 33 31543164. (https://doi.org/10.1093/nar/gki624)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • International Cancer Genome Consortium, Hudson TJ, Anderson W, Artez A, Barker AD, Bell C, Bernabé RR, Bhan MK, Calvo F & Eerola I et al.2010 International network of cancer genome projects. Nature 464 993998. (https://doi.org/10.1038/nature08987)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Inzani F, Petrone G & Rindi G 2018 The New World Health Organization classification for pancreatic neuroendocrine neoplasia. Endocrinology and Metabolism Clinics of North America 47 463470. (https://doi.org/10.1016/j.ecl.2018.04.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kolde R 2015 pheatmap: pretty heatmaps. R package version 1.0.8, pp. 17. (available at: https://CRAN.R-project.org/package=pheatmap)

  • Kuo T, Kim-Muller JY, McGraw TE & Accili D 2016 Altered plasma profile of antioxidant proteins as an early correlate of pancreatic β cell dysfunction. Journal of Biological Chemistry 291 96489656. (https://doi.org/10.1074/jbc.M115.702183)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lepage C, Bouvier AM & Faivre J 2013 Endocrine tumours: epidemiology of malignant digestive neuroendocrine tumours. European Journal of Endocrinology 168 R77R83. (https://doi.org/10.1530/EJE-12-0418)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin H & Zelterman D 2002 Modeling Survival Data: Extending the Cox Model. New York: Springer. (https://doi.org/10.1198/tech.2002.s656)

  • Manfredi S, Walter T, Baudin E, Coriat R, Ruszniewski P, Lecomte T, Laurenty AP, Goichot B, Rohmer V & Roquin G et al.2017 Management of gastric neuro-endocrine tumours in a large French national cohort (GTE). Endocrine 57 504511. (https://doi.org/10.1007/s12020-017-1355-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mehrabi A, Fischer L, Hafezi M, Dirlewanger A, Grenacher L, Diener MK, Fonouni H, Golriz M, Garoussi C & Fard N et al.2014 A systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas 43 675686. (https://doi.org/10.1097/MPA.0000000000000110)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mendel DB & Crabtree GR 1991 HNF-1, a member of a novel class of dimerizing homeodomain proteins. Journal of Biological Chemistry 266 677680. (https://doi.org/10.1016/s0021-9258(17)35222-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, Della Peruta M, Piemonti L, Capurso G, Di Florio A & Delle Fave G et al.2010 Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. Journal of Clinical Oncology 28 245255. (https://doi.org/10.1200/JCO.2008.21.5988)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Muraro MJ, Dharmadhikari G, Grün D, Groen N, Dielen T, Jansen E, van Gurp L, Engelse MA, Carlotti F & de Koning EJP et al.2016 A single-cell transcriptome atlas of the human pancreas. Cell Systems 3 385 .e3394.e3. (https://doi.org/10.1016/j.cels.2016.09.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nuñez-Valdovinos B, Carmona-Bayonas A, Jimenez-Fonseca P, Capdevila J, Castaño-Pascual Á, Benavent M, Pi Barrio JJ, Teule A, Alonso V & Custodio A et al.2018 Neuroendocrine tumor heterogeneity adds uncertainty to the World Health Organization 2010 classification: real-world data from the Spanish tumor registry (R-GETNE). Oncologist 23 422432. (https://doi.org/10.1634/theoncologist.2017-0364)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • R Development Core Team 3.0.1 2013 A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, p. 2. (available at: https://www.R-project.org)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ramond C, Beydag-Tasöz BS, Azad A, van de Bunt M, Petersen MBK, Beer NL, Glaser N, Berthault C, Gloyn AL & Hansson M et al.2018 Understanding human fetal pancreas development using subpopulation sorting, RNA sequencing and single-cell profiling. Development 145 dev165480. (https://doi.org/10.1242/dev.165480)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rodríguez-Seguel E, Mah N, Naumann H, Pongrac IM, Cerdá-Esteban N, Fontaine JF, Wang Y, Chen W, Andrade-Navarro MA & Spagnoli FM 2013 Mutually exclusive signaling signatures define the hepatic and pancreatic progenitor cell lineage divergence. Genes and Development 27 19321946. (https://doi.org/10.1101/gad.220244.113)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sadanandam A, Wullschleger S, Lyssiotis CA, Grötzinger C, Barbi S, Bersani S, Körner J, Wafy I, Mafficini A & Lawlo RT et al.2015 A cross-species analysis in pancreatic neuroendocrine tumors reveals molecular subtypes with distinctive clinical, metastatic, developmental, and metabolic characteristics. Cancer Discovery 5 12961313. (https://doi.org/10.1158/2159-8290.CD-15-0068)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, Bailey P, Lawlor RT, Johns AL, Miller DK & Mafficini A et al.2017 Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 543 6571. (https://doi.org/10.1038/nature21063)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Segerstolpe Å, Palasantza A, Eliasson P, Andersson EM, Andreasson AC, Sun X, Picelli S, Sabirsh A, Clausen M & Bjursell MK et al.2016 Single-cell transcriptome profiling of human pancreatic islets in health and Type 2 diabetes. Cell Metabolism 24 593607. (https://doi.org/10.1016/j.cmet.2016.08.020)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Seok JY, Na DC, Woo HG, Roncalli M, Kwon SM, Yoo JE, Ahn EY, Kim GIl, Choi JS & Kim YB et al.2012 A fibrous stromal component in hepatocellular carcinoma reveals a cholangiocarcinoma-like gene expression trait and epithelial-mesenchymal transition. Hepatology 55 17761786. (https://doi.org/10.1002/hep.25570)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR & Lander ES et al.2005 Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. PNAS 102 1554515550. (https://doi.org/10.1073/pnas.0506580102)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E & Asplund A et al.2015 Proteomics. Tissue-based map of the human proteome. Science 347 1260419. (https://doi.org/10.1126/science.1260419)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang YJ, Schug J, Won KJ, Liu C, Naji A, Avrahami D, Golson ML & Kaestner KH 2016 Single-cell transcriptomics of the human endocrine pancreas. Diabetes 65 30283038. (https://doi.org/10.2337/db16-0405)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang B, Chen S, Qian H, Chen R, He Y, Zhang X, Xuan J, Liu Y & Shi G 2020 Development and validation of a transcriptional signature for the assessment of fibrosis in organs. MedRxiv [epub].(https://doi.org/10.1101/2020.03.14.20024141)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wickham H 2016 Ggplot2: Elegant Graphics for Data Analysis. New York, NY, USA: Springer-Verlag.

  • Worrall SF 2000 TNM classification of malignant tumours. British Journal of Oral and Maxillofacial Surgery 38 P244. (https://doi.org/10.1054/bjom.1999.0055)

  • Zhernakova DV, de Klerk E, Westra HJ, Mastrokolias A, Amini S, Ariyurek Y, Jansen R, Penninx BW, Hottenga JJ & Willemsen G et al.2013 DeepSAGE reveals genetic variants associated with alternative polyadenylation and expression of coding and non-coding transcripts. PLoS Genetics 9 e1003594. (https://doi.org/10.1371/journal.pgen.1003594)

    • PubMed
    • Search Google Scholar
    • Export Citation