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

• Published in: Nature communications Vol. 12; no. 1; p. 4612
• Main Authors: van Riet, Job, van de Werken, Harmen J. G., Cuppen, Edwin, Eskens, Ferry A. L. M., Tesselaar, Margot, van Veenendaal, Linde M., Klümpen, Heinz-Josef, Dercksen, Marcus W., Valk, Gerlof D., Lolkema, Martijn P., Sleijfer, Stefan, Mostert, Bianca
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.07.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/23; 49; 631/1647/514/2254; 631/208/69; 631/67/1459/1963; 631/67/395; Adenomatous polyposis coli; Aged; Daxx protein; Female; Gene sequencing; Genes, Neoplasm; Genomes; Genomics; Heterogeneity; Humanities and Social Sciences; Humans; Localization; Male; Metastases; Metastasis; Middle Aged; Midgut; multidisciplinary; Mutation; Myc protein; Neoplasm Staging; Neoplasms; Neuroendocrine tumors; Neuroendocrine Tumors - classification; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - metabolism; Neuroendocrine Tumors - pathology; p53 Protein; Pancreas; Prognosis; Science; Science (multidisciplinary); Subpopulations; Therapeutic applications; Tumors; Whole genome sequencing; Whole Genome Sequencing - methods
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24812-3

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. Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) display heterogeneous clinical and genetic characteristics. Here, the authors investigate the mutational landscape of 85 aNEN by whole genome sequencing and identify distinct subpopulations, tumour mutational burden patterns, drivers and actionable somatic alterations.