在整合型小鼠模型中早期TP53的变化与环境因素共同促进胃的癌变。这一成果由美国丹娜法伯癌症研究所Adam J. Bass和Nilay S. Sethi合作取得。相关论文在线发表在2020年2月5日的《自然—遗传学》上。

通过将早期的遗传改变与疾病相关的环境相结合，研究人员构建了整合型小鼠模型来研究胃的癌前病变。在饮食致癌物的环境中，胃细胞中Trp53的缺失赋予了癌细胞选择性优势并促进细胞的异常发育和发展。来自增生异常病变的类器官促进了对胃癌前病变的基因组、转录和功能评估。p53失活使得细胞周期调节剂在胃癌前期被上调，最著名的是Cdkn2a，这成为疾病发展的障碍。尽管在发育异常的胃类器官中的Cdkn2a和Trp53的双敲除促进了癌症表型，但也引起了复制压力，使其对DNA损伤抑制剂敏感。这些发现表明基因组改变与相关环境相结合的小鼠模型具有实用性，并突出了基因与环境相互作用在细胞恶变重塑前的重要性。

研究人员表示，在正常和恶变前组织中都检测到了体细胞中癌基因的变化，因此人们应更加重视能够促进疾病表型的基因-环境相互作用。

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