In-depth analysis of the genomic landscape of 86 metastatic neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets

Abstract

Metastatic neuroendocrine neoplasms (mNEN) 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 86 whole-genome sequenced mNEN. This landscape revealed distinct genomic subpopulations of mNEN based on primary localization and differentiation grade; we observed relatively high tumor mutational burdens (TMB) in neuroendocrine carcinoma (5.45 somatic mutations per megabase) with TP53, KRAS, RB1, MYC and APC as major drivers versus an overall low TMB in neuroendocrine tumors (1.08). Furthermore, we observed distinct drivers which were enriched with somatic aberrations in pancreatic (MEN1, ATRX, DAXX, PCNT and SETD2) and midgut-derived neuroendocrine tumors (CDKN1B). Finally, 49% of mNEN patients revealed extensions of their treatment-repertoire based upon actionable (and responsive) somatic aberrations; potentially directing improvements in mNEN treatment strategies.