Metastatic timing and genetic heterogeneity in the evolution of a pancreatic neuroendocrine tumor

Xia Tang*, Yue Shao*, Xin Yi, Paul J. Newey, Dewei Li$, Keyue Ding$, and Gastrointestinal Cancer Evolution Study Group

*Authors share co-first authorship; $Authors share co-senior authorship

#: Corresponding authors Keyue Ding, PhD, E-mail:; or Dewei Li, MD, E-mail:


Pancreatic neuroendocrine tumors (PanNETs) account for 1-2% of all pancreatic cancers and are frequently diagnosed at a point at which metastatic deposits to local lymph nodes (LNs) and the liver are evident. However, the disease course of PanNETs remains highly variable, and accurate predictors of prognosis and treatment response are not available. Although recent studies have identified a number of recurrently mutated driver genes implicated in PanNET development, the molecular events resulting in the acquisition of metastatic potential and subsequently during tumor progression remain to be defined. Here, we present the case of a patient with metastatic PanNET, in whom serial tumor samples were obtained over a ~13-year period. Using whole-exome sequencing, we observed significant genetic heterogeneity between primary and metastatic tumor samples. Although all tumor samples shared somatic mutations in key driver genes including MEN1, DAXX and TSC2, a hypermutation phenotype was observed in the primary tumor, which was not shared with LN or hepatic metastases, indicating that seeding of metastatic tumor clones likely occurred before the hypermutation accumulation in the disease course. In addition, phylogenetic analysis indicated the presence of polyclonal metastatic seeding by both linear and branching spread patterns. This study provides unique insight into the genetic forces shaping metastatic spread in PanNETs and has important implications for the development of therapeutic strategies.


The Gastrointestinal Cancer Evolution Study Group include: Liujun Jiang, Liang Chen, Zixin Chen and Lei Xiang, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing; Xinmei Wang, Department of Pathology, School of Basic Medicine, Chongqing Medical University, Chongqing; Fajin Lv, Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing; Shasha Bian and Bingtao Hao, Medical Genetic Institute of Henan Province, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Henan Provincial People’s Hospital, Zhengzhou, Henan; and Yanfang Guan, and Rongrong Chen, Geneplus-Beijing Institute, Beijing.