Smith Lucian P, Yamato Jon A, Galipeau Patricia C, Paulson Thomas G, Li Xiaohong, Sanchez Carissa A, Reid Brian J, Kuhner Mary K
Department of Genome Sciences University of Washington Seattle WA USA.
Division of Human Biology Fred Hutchinson Cancer Research Center Seattle WA USA.
Evol Appl. 2020 Sep 20;14(2):399-415. doi: 10.1111/eva.13125. eCollection 2021 Feb.
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 of and showed 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 of and mutant lineages during initial growth of the segment, followed by relative stasis. Subsequent to initial expansion, mutations in these loci as well as and may 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.
巴雷特食管是一种肿瘤性疾病，在5%的病例中会发展为食管腺癌。影响预后的关键事件可能发生在巴雷特食管诊断之前，且无法直接观察到；我们使用系统发育分析来推断此类过去的事件。我们对40例癌症预后和40例非癌症预后的巴雷特食管患者的4 - 6个样本进行了全基因组测序，并推断了解卷积克隆谱系的患者内系统发育。在系统发育中，空间上相邻的谱系聚集在一起，但时间上相邻的谱系并非如此。在 和 的两个拷贝中均具有推断的功能丧失突变的谱系显示出增强的空间扩散，而在其他频繁突变位点具有功能丧失突变的谱系则没有。我们提出了一个两阶段模型，在该节段初始生长期间 和 突变谱系扩张，随后相对静止。在初始扩张之后，这些位点以及 和 的突变可能显示出局部选择优势，但不会扩散太远：即使在发展为癌症的患者中，巴雷特节段的空间结构在监测期间仍保持稳定。我们得出结论，癌症/非癌症预后受到巴雷特节段形成早期步骤的强烈影响。
