Multi-omic cross-sectional cohort study of pre-malignant Barrett’s esophagus reveals early structural variation and retrotransposon activity

A. C. Katz-Summercorn, S. Jammula, A. Frangou, I. Peneva, M. O’Donovan, M. Tripathi, S. Malhotra, M. Pietro, S. Abbas, G. Devonshire, W. Januszewicz, A. Blasko, K. Nowicki-Osuch, S. MacRae, A. Northrop, A. M. Redmond, D. C. Wedge and R. C. Fitzgerald ()
Additional contact information
A. C. Katz-Summercorn: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
S. Jammula: Cancer Research UK Cambridge Institute, University of Cambridge
A. Frangou: Wellcome Centre for Human Genetics, University of Oxford
I. Peneva: Wellcome Centre for Human Genetics, University of Oxford
M. O’Donovan: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
M. Tripathi: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
S. Malhotra: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
M. Pietro: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
S. Abbas: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
G. Devonshire: Cancer Research UK Cambridge Institute, University of Cambridge
W. Januszewicz: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
A. Blasko: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
K. Nowicki-Osuch: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
S. MacRae: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
A. Northrop: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
A. M. Redmond: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge
D. C. Wedge: Manchester Cancer Research Centre, University of Manchester
R. C. Fitzgerald: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Barrett’s esophagus is a pre-malignant lesion that can progress to esophageal adenocarcinoma. We perform a multi-omic analysis of pre-cancer samples from 146 patients with a range of outcomes, comprising 642 person years of follow-up. Whole genome sequencing reveals complex structural variants and LINE-1 retrotransposons, as well as known copy number changes, occurring even prior to dysplasia. The structural variant burden captures the most variance across the cohort and genomic profiles do not always match consensus clinical pathology dysplasia grades. Increasing structural variant burden is associated with: high levels of chromothripsis and breakage-fusion-bridge events; increased expression of genes related to cell cycle checkpoint, DNA repair and chromosomal instability; and epigenetic silencing of Wnt signalling and cell cycle genes. Timing analysis reveals molecular events triggering genomic instability with more clonal expansion in dysplastic samples. Overall genomic complexity occurs early in the Barrett’s natural history and may inform the potential for cancer beyond the clinically discernible phenotype.

Date: 2022
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DOI: 10.1038/s41467-022-28237-4

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