TP53突變與環(huán)境因素共同促進(jìn)胃癌變
在整合型小鼠模型中早期TP53的變化與環(huán)境因素共同促進(jìn)胃的癌變。這一成果由美國丹娜法伯癌癥研究所Adam J. Bass和Nilay S. Sethi合作取得。相關(guān)論文在線發(fā)表在2020年2月5日的《自然—遺傳學(xué)》上。
通過將早期的遺傳改變與疾病相關(guān)的環(huán)境相結(jié)合，研究人員構(gòu)建了整合型小鼠模型來研究胃的癌前病變。在飲食致癌物的環(huán)境中，胃細(xì)胞中Trp53的缺失賦予了癌細(xì)胞選擇性優(yōu)勢并促進(jìn)細(xì)胞的異常發(fā)育和發(fā)展。來自增生異常病變的類器官促進(jìn)了對胃癌前病變的基因組、轉(zhuǎn)錄和功能評估。p53失活使得細(xì)胞周期調(diào)節(jié)劑在胃癌前期被上調(diào)，知名的是Cdkn2a，這成為疾病發(fā)展的障礙。盡管在發(fā)育異常的胃類器官中的Cdkn2a和Trp53的雙敲除促進(jìn)了癌癥表型，但也引起了復(fù)制壓力，使其對DNA損傷抑制劑敏感。這些發(fā)現(xiàn)表明基因組改變與相關(guān)環(huán)境相結(jié)合的小鼠模型具有實用性，并突出了基因與環(huán)境相互作用在細(xì)胞惡變重塑前的重要性。
研究人員表示，在正常和惡變前組織中都檢測到了體細(xì)胞中癌基因的變化，因此人們應(yīng)更加重視能夠促進(jìn)疾病表型的基因-環(huán)境相互作用。
附：英文原文
Title: Early TP53 alterations engage environmental exposures to promote gastric premalignancy in an integrative mouse model
Author: Nilay S. Sethi, Osamu Kikuchi, Gina N. Duronio, Matthew D. Stachler, James M. McFarland, Ruben Ferrer-Luna, Yanxi Zhang, Chunyang Bao, Roderick Bronson, Deepa Patil, Francisco Sanchez-Vega, Jie-Bin Liu, Ewa Sicinska, Jean-Bernard Lazaro, Keith L. Ligon, Rameen Beroukhim, Adam J. Bass
Issue&Volume: 2020-02-05
Abstract: Somatic alterations in cancer genes are being detected in normal and premalignant tissue, thus placing greater emphasis on gene–environment interactions that enable disease phenotypes. By combining early genetic alterations with disease-relevant exposures, we developed an integrative mouse model to study gastric premalignancy. Deletion of Trp53 in gastric cells confers a selective advantage and promotes the development of dysplasia in the setting of dietary carcinogens. Organoid derivation from dysplastic lesions facilitated genomic, transcriptional and functional evaluation of gastric premalignancy. Cell cycle regulators, most notably Cdkn2a, were upregulated by p53 inactivation in gastric premalignancy, serving as a barrier to disease progression. Co-deletion of Cdkn2a and Trp53 in dysplastic gastric organoids promoted cancer phenotypes but also induced replication stress, exposing a susceptibility to DNA damage response inhibitors. These findings demonstrate the utility of mouse models that integrate genomic alterations with relevant exposures and highlight the importance of gene–environment interactions in shaping the premalignant state.
DOI: 10.1038/s41588-019-0574-9
Source: https://www.nature.com/articles/s41588-019-0574-9
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