Clonal Diaspora in Metastatic Esophageal Adenocarcinoma Describes a New Model of Cancer Progression

Continual evolution of cancer on a microscopic scale makes accurate clinical assessment challenging. The highly varied and unpredictable patient outcomes in esophageal adenocarcinoma (EAC) prompted us to question conventional modes of metastatic spread. Whole genome sequencing and phylogenetic analysis of 396 samples across 18 EAC cases demonstrated contemporaneous polyclonal seeding from the primary to multiple disparate sites at a single time-point in 90% cases- so-called clonal diaspora. The age-dependent trinucleotide signature was rarely observed post diaspora supporting a near-synchronous metastatic seeding process. Clustering of lymph nodes and distant metastases (n=250) demonstrated that samples sharing a common clonal origin were widely dispersed spatially. Metastatic subclones at autopsy were present in the primary tumor at diagnosis, and in blood samples at earlier time-points. This is consistent with our hypothesis that metastasis occurs at a single time-point and has far-reaching implications of our understanding of metastatic progression, clinical staging and patient management.