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

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>TP53</jats:italic>, <jats:italic>KRAS</jats:italic>, <jats:italic>RB1</jats:italic>, <jats:italic>CSMD3</jats:italic>, <jats:italic>APC</jats:italic>, <jats:italic>CSMD1</jats:italic>, <jats:italic>LRATD2</jats:italic>, <jats:italic>TRRAP and MYC</jats:italic> 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 (<jats:italic>MEN1</jats:italic>, <jats:italic>ATRX</jats:italic>, <jats:italic>DAXX</jats:italic>, <jats:italic>DMD</jats:italic> and <jats:italic>CREBBP</jats:italic>) and midgut-derived neuroendocrine tumors (<jats:italic>CDKN1B</jats:italic>). 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.</jats:p>