美国纪念斯隆-凯特琳癌症中心Scott W. Lowe团队揭示出p53缺失后的有序和确定性的癌症基因组演化。相关论文于2022年8月17日在线发表在《自然》杂志上。

在一个胰腺导管腺癌的小鼠模型中（在癌症发病前报告了零星的p53杂合度丢失），研究人员发现p53失活所带来的恶性特性是通过可预测的基因组演化模式获得的。单细胞测序和原位基因分型显示，从p53失活到发展为真正的癌症，这种确定性的行为涉及四个连续的阶段：rp53（编码小鼠p53）杂合度的丧失、缺失的积累、基因组加倍以及增益和扩增的出现，每个阶段都与整个恶性肿瘤前期和恶性肿瘤的特定组织学阶段有关。

尽管异质性很强，但p53失活后的缺失事件以功能相关的途径为目标，可以塑造基因组的演化，并在不同的恶性肿瘤群体中保持固定的同质性事件。因此，p53的丧失（"基因组的守护者"）不仅仅是通向遗传混乱的大门，相反，它可以使基因组演化的确定性模式成为可能，从而为治疗TP53突变的肿瘤指明新的策略。

据介绍，尽管p53失活促进了基因组的不稳定性，并为超过一半的人类癌症提供了通往恶性的途径，但对异源性TP53（编码人类p53）突变体基因组的出现和影响肿瘤发生的模式仍知之甚少。

附：英文原文

Title: Ordered and deterministic cancer genome evolution after p53 loss

Author: Baslan, Timour, Morris, John P., Zhao, Zhen, Reyes, Jose, Ho, Yu-Jui, Tsanov, Kaloyan M., Bermeo, Jonathan, Tian, Sha, Zhang, Sean, Askan, Gokce, Yavas, Aslihan, Lecomte, Nicolas, Erakky, Amanda, Varghese, Anna M., Zhang, Amy, Kendall, Jude, Ghiban, Elena, Chorbadjiev, Lubomir, Wu, Jie, Dimitrova, Nevenka, Chadalavada, Kalyani, Nanjangud, Gouri J., Bandlamudi, Chaitanya, Gong, Yixiao, Donoghue, Mark T. A., Socci, Nicholas D., Krasnitz, Alex, Notta, Faiyaz, Leach, Steve D., Iacobuzio-Donahue, Christine A., Lowe, Scott W.

Issue&Volume: 2022-08-17

Abstract: Although p53 inactivation promotes genomic instability1 and presents a route to malignancy for more than half of all human cancers2,3, the patterns through which heterogenous TP53 (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases—Trp53 (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications—each associated with specific histological stages across the premalignant and malignant spectrum. Despite rampant heterogeneity, the deletion events that follow p53 inactivation target functionally relevant pathways that can shape genomic evolution and remain fixed as homogenous events in diverse malignant populations. Thus, loss of p53—the ‘guardian of the genome’—is not merely a gateway to genetic chaos but, rather, can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of TP53-mutant tumours.

DOI: 10.1038/s41586-022-05082-5

Source: https://www.nature.com/articles/s41586-022-05082-5