英国威康桑格研究所Jones, Philip H.研究小组发现,Notch1突变驱动正常食管上皮细胞克隆扩增,但损害肿瘤生长。该项研究成果于2023年1月19日在线发表在《自然—遗传学》杂志上。
据研究人员介绍,NOTCH1突变克隆在中年正常人食管癌中占大多数,但在食管癌中相对罕见,这表明NOTCH1突变驱动克隆扩增但阻碍癌变。
附:英文原文
Title: Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth
Author: Abby, Emilie, Dentro, Stefan C., Hall, Michael W. J., Fowler, Joanna C., Ong, Swee Hoe, Sood, Roshan, Herms, Albert, Piedrafita, Gabriel, Abnizova, Irina, Siebel, Christian W., Gerstung, Moritz, Hall, Benjamin A., Jones, Philip H.
Issue&Volume: 2023-01-19
Abstract: NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.
DOI: 10.1038/s41588-022-01280-z
Source: https://www.nature.com/articles/s41588-022-01280-z
Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex
本期文章:《自然—遗传学》:Online/在线发表