The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets.
Job van RietHarmen J G van de WerkenEdwin CuppenFerry A L M EskensMargot TesselaarLinde M van VeenendaalHeinz-Josef KlümpenMarcus W DercksenGerlof D ValkMartijn Paul LolkemaStefan SleijferBianca MostertPublished in: Nature communications (2021)
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.
Keyphrases
- neuroendocrine tumors
- copy number
- single cell
- genome wide
- squamous cell carcinoma
- locally advanced
- end stage renal disease
- ejection fraction
- dna methylation
- newly diagnosed
- small cell lung cancer
- peritoneal dialysis
- type diabetes
- duchenne muscular dystrophy
- transcription factor
- patient reported outcomes
- skeletal muscle
- gene expression
- radiation therapy
- lymph node
- insulin resistance
- risk assessment
- replacement therapy
- wild type
- muscular dystrophy