The Evolutionary History of Metastatic Pancreatic Neuroendocrine Tumours Reveals a Therapy Driven Route to High-Grade Transformation.
Samuel BackmanJohan BotlingHelena NordSuman GhosalPeter StålbergC Christofer JuhlinJonas AlmlöfAnders SundinLiang ZhangLotte MoensBarbro ErikssonStaffan WelinPer HellmanBritt SkogseidKarel PacakKazhan MollazadeganTobias ÅkerströmJoakim CronaPublished in: medRxiv : the preprint server for health sciences (2024)
Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular, show frequent progression from a low/intermediate to a high-grade disease. To understand the molecular mechanisms underlying this phenomenon, we performed multi-omics analysis of 32 longitudinal samples from six metastatic PanNET patients. Following MEN1 inactivation, PanNETs exhibit genetic heterogeneity on both spatial and temporal dimensions with parallel and convergent tumuor evolution involving the ATRX/DAXX and mTOR pathways. Following alkylating chemotherapy treatment, some PanNETs develop mismatch repair deficiency and acquire a hypermutator phenotype. This DNA hypermutation phenotype was only found in cases that also showed transformation into a high-grade PanNET. Overall, our findings contribute to broaden the understanding of metastatic PanNET, and suggests that therapy driven disease evolution is an important hallmark of this disease.
Keyphrases
- high grade
- squamous cell carcinoma
- small cell lung cancer
- low grade
- single cell
- end stage renal disease
- cell proliferation
- newly diagnosed
- stem cells
- genome wide
- dna methylation
- gene expression
- ejection fraction
- single molecule
- prognostic factors
- peritoneal dialysis
- replacement therapy
- radiation therapy
- cross sectional
- cell free
- mesenchymal stem cells
- young adults
- circulating tumor cells