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.

转移性和局部晚期神经内分泌肿瘤 (aNEN) 形成临床和遗传异质性恶性肿瘤，其特征在于基于原发肿瘤定位、功能、分级、增殖指数和不同治疗结果的不同预后。在这里，我们报告了 85 个全基因组测序的 aNEN 的突变情况。这种景观揭示了基于初级定位和分化等级的 aNEN 的不同基因组亚群；我们观察到在神经内分泌癌相对高的肿瘤突变负担（TMB）（平均每兆碱基5.45的体细胞突变）与TP53，KRAS，RB1，CSMD3，APC，CSMD1，LRATD2，TRRAP 和 MYC作为主要驱动因素，而神经内分泌肿瘤中 TMB 总体较低 (1.09)。此外，我们观察到在胰腺（MEN1、ATRX、DAXX、DMD和CREBBP）和中肠源性神经内分泌肿瘤（CDKN1B）中富含体细胞畸变的不同驱动因素。最后，49% 的 aNEN 患者根据其基因组内的可操作（和响应）体细胞畸变揭示了潜在的治疗目标；潜在指导改进 aNEN 治疗策略。