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

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 Sleijfer and Bianca Mostert ()
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Job Riet: University Medical Center
Harmen J. G. Werken: University Medical Center
Edwin Cuppen: University Medical Center Utrecht
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
Stefan Sleijfer: Erasmus MC Cancer Institute
Bianca Mostert: Erasmus MC Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24812-3

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DOI: 10.1038/s41467-021-24812-3

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