Somatic whole genome dynamics of precancer in Barrett’s esophagus reveals features associated with disease progression

While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett’s esophagus compared to 40 Barrett’s patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes are active in Barrett’s tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett’s versus those who progress to cancer is acquisition and expansion of TP53-/- cell populations having complex structural variants and high-level amplifications, which are detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett’s esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies.

Nat Commun. 2022 Apr 28;13(1):2300

PMID: 35484108 PMCID: PMC9050715  DOI: 10.1038/s41467-022-29767-7


Other Contributors

Thomas G Paulson # 1, Patricia C Galipeau # 2, Kenji M Oman 2, Carissa A Sanchez 2, Mary K Kuhner 3 4, Lucian P Smith 3, Kevin Hadi 5, Minita Shah 5, Kanika Arora 5, Jennifer Shelton 5, Molly Johnson 5, Andre Corvelo 5, Carlo C Maley 6, Xiaotong Yao 5, Rashesh Sanghvi 5, Elisa Venturini 5, Anne-Katrin Emde 7, Benjamin Hubert 5, Marcin Imielinski 5 8, Nicolas Robine 5, Brian J Reid 2 3 4 9, Xiaohong Li 10


  • 1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
  • 2Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
  • 3Department of Genome Sciences, University of Washington, Seattle, WA, 98195-5065, USA.
  • 4Brotman Baty Institute for Precision Medicine, Seattle, WA, 98195-5065, USA.
  • 5New York Genome Center (NYGC), New York, NY, 10013, USA.
  • 6Arizona Cancer Evolution Center, Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, 85281, USA.
  • 7Variant Bio, Brooklyn, NY, 11205, USA.
  • 8Department of Pathology and Laboratory Medicine, Englander Institute for Precision Medicine, Institute for Computational Biomedicine and Meyer Cancer Center, Weill Cornell Medical College, New York, NY, 10065, USA.
  • 9Department of Medicine, University of Washington, Seattle, WA, 98195, USA.
  • 10Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
#Contributed equally.