Abstract
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.
Highlights
Metastatic and locally-advanced neuroendocrine neoplasms form clinically and genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, functionality, grade, proliferation index and diverse outcomes to treatment
A total of 108 patients, originally classified as having a neuroendocrine neoplasm, were included in the Center for Personalized Cancer Treatment (CPCT)-02 and DRUP studies and had a primary or metastatic tumor biopsy taken in parallel with a blood control (Fig. 1)
ANET is characterized by the lowest tumor mutational burdens (TMB) of all metastatic cohorts sequenced in the CPCT-02 study[27]
Summary
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. Associated genetic drivers of NET include the cell-cycle regulator CDKN1B in SINET10–13, chromatin-remodeling genes (DAXX, ATRX, MEN1, and SETD2), DNA-repair genes (CHEK2, BRCA2, and MUTYH), mTOR-related genes (TSC2, PTEN, and PIK3CA) and the oxygen-sensing modulator VHL14 in pNET3–5,7,15 whilst NEC is associated with aberrations in TP53, RB1, MYC, CCND1, KRAS, PIK3CA/PTEN and BRAF9,16–18 These studies were all performed on primary tumor specimens, whilst a patient generally dies from the consequences of metastatic disease. We investigate the presence of actionable genetic alteration within aNEN patients, which might render them eligible for off-label or experimental systemic treatments to extend therapy options
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