期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：47
DOI：10.1073/pnas.2113061118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Barrett’s esophagus (BE), the premalignant condition of esophageal adenocarcinoma, is categorized into different stages which correlate with the risk of developing carcinoma. We performed single-cell DNA-sequencing experiments with fresh biopsies, which revealed the appearance of a specific T > C and T > G mutational signature, known as COSMIC signature SBS17, in BE cells that are chromosomally unstable. The SBS17-specific mutations were, however, not detected in chromosomally stable BE cells. Additionally, we performed single-cell RNA sequencing experiments which identified seven genes that facilitate the distinction between different BE stages on histological sections.
Barrett’s esophagus (BE) is categorized, based on morphological appearance, into different stages, which correlate with the risk of developing esophageal adenocarcinoma. More advanced stages are more likely to acquire chromosomal instabilities, but stage-specific markers remain elusive. Here, we performed single-cell DNA-sequencing experiments (scDNAseq) with fresh BE biopsies. Dysplastic BE cells frequently contained chromosomal instability (CIN) regions, and these CIN cells carried mutations corresponding to the COSMIC mutational signature SBS17, which were not present in biopsy-matched chromosomally stable (CS) cells or patient-matched nondiseased control cells. CS cells were predominantly found in nondysplastic BE biopsies. The single-base substitution (SBS) signatures of all CS BE cells analyzed were indistinguishable from those of nondiseased esophageal or gastric cells. Single-cell RNA-sequencing (scRNAseq) experiments with BE biopsies identified two sets of marker genes which facilitate the distinction between columnar BE epithelium and nondysplastic/dysplastic stages. Moreover, histological validation confirmed a correlation between increased CLDN2 expression and the presence of dysplastic BE stages. Our scDNAseq and scRNAseq datasets, which are a useful resource for the community, provide insight into the mutational landscape and gene expression pattern at different stages of BE development.
关键词：Barrett’s esophagus; single-cell RNA and DNA analyses; single-base substitution 17 (SBS17a and SBS17b)
