Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) form clinically andgenetically heterogeneous malignancies, characterized by distinct prognoses based uponprimary tumor localization, functionality, grade, proliferation index and diverse outcomes totreatment. 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 overalllow TMB in neuroendocrine tumors (1.09). [...]