Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma

Ayesha Noorani; Xiaodun Li; Martin J Goddard; Jason Crawte; Ludmil B. Alexandrov; Maria Secrier; Matthew Eldridge; Lawrence Bower; Jamie M. J. Weaver; Pierre Lao-Sirieix; Iñigo Martincorena; Irene Debiram–Beecham; Nicola Grehan; Shona MacRae; Shalini Malhotra; Ahmad Miremadi; Tabitha Thomas; Sarah Galbraith; Christopher John Peters; Stephen Preston; David Gilligan; Andrew Hindmarsh; Richard Henry Hardwick; Michael R. Stratton; David C. Wedge; Rebecca Claire Fitzgerald

doi:10.1038/s41588-019-0551-3

GenomicsNature GeneticsJan 1, 2020

Peer-reviewed journal article

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma

Ayesha Noorani, Xiaodun Li iD, Martin J Goddard iD, Jason Crawte iD, Ludmil B. Alexandrov iD, Maria Secrier iD, Matthew Eldridge iD, Lawrence Bower iD, Jamie M. J. Weaver iD, Pierre Lao-Sirieix, Iñigo Martincorena iD, Irene Debiram–Beecham iD, Nicola Grehan, Shona MacRae, Shalini Malhotra iD, Ahmad Miremadi, Tabitha Thomas iD, Sarah Galbraith iD, Christopher John Peters iD, Stephen Preston iD, David Gilligan iD, Andrew Hindmarsh iD, Richard Henry Hardwick iD, Michael R. Stratton iD, David C. Wedge iD, Rebecca Claire Fitzgerald iD

Abstract

Continual evolution of cancer makes it challenging to predict clinical outcomes. Highly varied and unpredictable patient outcomes in esophageal adenocarcinoma (EAC) prompted us to question the pattern and timing of metastatic spread. Whole genome sequencing and phylogenetic analysis of 396 samples across 18 EAC cases demonstrated a stellate pattern on the phylogenetic trees in 90% cases. The age-dependent trinucleotide signature, which can serve as a molecular clock, was absent or reduced in the stellate branches beyond the trunk in most cases (p<0.0001). Clustering of lymph nodes and distant metastases (n=250) demonstrated samples sharing a common clonal origin were widely dispersed anatomically. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time-points. We infer that metastasis occurs rapidly across multiple sites, constituting a model of metastatic spread we term clonal diaspora. This has implications for understanding metastatic progression, clinical staging and patient management.

PDF DOI