期刊
EVOLUTIONARY APPLICATIONS
卷 14, 期 2, 页码 399-415出版社
WILEY
DOI: 10.1111/eva.13125
关键词
ARID1A; Barrett's Esophagus; CDKN2A; esophageal adenocarcinoma; genome doubling; phylogeny; SMARCA4; subclonality; TP53
资金
- National Cancer Institute [CA015704, CA140657, CA91955]
Barrett's Esophagus is a neoplastic condition that can progress to esophageal adenocarcinoma. Early steps in the formation of the Barrett's segment strongly influence whether patients will develop cancer in the future.
Barrett's Esophagus is a neoplastic condition which progresses to esophageal adenocarcinoma in 5% of cases. Key events affecting the outcome likely occur before diagnosis of Barrett's and cannot be directly observed; we use phylogenetic analysis to infer such past events. We performed whole-genome sequencing on 4-6 samples from 40 cancer outcome and 40 noncancer outcome patients with Barrett's Esophagus, and inferred within-patient phylogenies of deconvoluted clonal lineages. Spatially proximate lineages clustered in the phylogenies, but temporally proximate ones did not. Lineages with inferred loss-of-function mutations in both copies ofTP53andCDKN2Ashowed enhanced spatial spread, whereas lineages with loss-of-function mutations in other frequently mutated loci did not. We propose a two-phase model with expansions ofTP53andCKDN2Amutant lineages during initial growth of the segment, followed by relative stasis. Subsequent to initial expansion, mutations in these loci as well asARID1AandSMARCA4may show a local selective advantage but do not expand far: The spatial structure of the Barrett's segment remains stable during surveillance even in patients who go on to cancer. We conclude that the cancer/noncancer outcome is strongly affected by early steps in formation of the Barrett's segment.
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