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The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets

Author

Listed:
  • Job Riet

    (University Medical Center
    University Medical Center
    Erasmus MC Cancer Institute)

  • Harmen J. G. Werken

    (University Medical Center
    University Medical Center)

  • Edwin Cuppen

    (University Medical Center Utrecht
    Hartwig Medical Foundation)

  • Ferry A. L. M. Eskens

    (Erasmus MC Cancer Institute)

  • Margot Tesselaar

    (University of Amsterdam)

  • Linde M. Veenendaal

    (University of Amsterdam)

  • Heinz-Josef Klümpen

    (Amsterdam University Medical Centers, Cancer Center Amsterdam)

  • Marcus W. Dercksen

    (Maxima Medisch Centrum)

  • Gerlof D. Valk

    (University Medical Center Utrecht)

  • Martijn P. Lolkema

    (Erasmus MC Cancer Institute
    Center for Personalized Cancer Treatment)

  • Stefan Sleijfer

    (Erasmus MC Cancer Institute
    Center for Personalized Cancer Treatment)

  • Bianca Mostert

    (Erasmus MC Cancer Institute)

Abstract

Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) form clinically and genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, functionality, grade, proliferation index and diverse outcomes to treatment. Here, we report the mutational landscape of 85 whole-genome sequenced aNEN. This landscape reveals distinct genomic subpopulations of aNEN based on primary localization and differentiation grade; we observe relatively high tumor mutational burdens (TMB) in neuroendocrine carcinoma (average 5.45 somatic mutations per megabase) with TP53, KRAS, RB1, CSMD3, APC, CSMD1, LRATD2, TRRAP and MYC as major drivers versus an overall low TMB in neuroendocrine tumors (1.09). Furthermore, we observe distinct drivers which are enriched in somatic aberrations in pancreatic (MEN1, ATRX, DAXX, DMD and CREBBP) and midgut-derived neuroendocrine tumors (CDKN1B). Finally, 49% of aNEN patients reveal potential therapeutic targets based upon actionable (and responsive) somatic aberrations within their genome; potentially directing improvements in aNEN treatment strategies.

Suggested Citation

  • Job Riet & Harmen J. G. Werken & Edwin Cuppen & Ferry A. L. M. Eskens & Margot Tesselaar & Linde M. Veenendaal & Heinz-Josef Klümpen & Marcus W. Dercksen & Gerlof D. Valk & Martijn P. Lolkema & Stefan, 2021. "The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24812-3
    DOI: 10.1038/s41467-021-24812-3
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