Ordered and deterministic cancer genome evolution after p53 loss.
Ordered and deterministic cancer genome evolution after p53 loss.
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DOI：
10.1038/s41586-022-05082-5
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发表时间：
2022-08
期刊：
影响因子：
64.8
通讯作者：
Lowe, Scott W.
中科院分区：
文献类型：
--
作者：
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.
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一条恶性转化的途径，但异源TP53(编码人类P53)突变基因组的出现并影响肿瘤发生的模式仍然知之甚少。在这里，在胰腺导管腺癌的小鼠模型中，在癌症发病前报告零星的P53杂合性丢失，我们发现通过可预测的基因组进化模式获得由P53失活实现的恶性特性。单细胞测序和对从p53失活到进展到直肠癌的细胞的原位基因分型显示，这种确定性行为涉及四个连续的阶段-Trp53(编码小鼠p53)杂合性丧失、缺失累积、基因组倍增以及获得和扩增的出现--每个阶段都与癌前和恶性光谱中特定的组织学阶段有关。尽管存在严重的异质性，但P53失活后的缺失事件针对的是功能相关的通路，这些通路可以塑造基因组进化，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基因的缺失不仅是导致基因混乱的原因，而且还可能导致基因组进化的确定性模式，这可能会为治疗突变的肿瘤提供新的策略。由P53失活所致的小鼠恶性进化是通过TrP53杂合性丢失、缺失积累、基因组加倍以及出现获得和扩增的有序和可预测的模式进行的。
Although p53 inactivation promotes genomic instability and presents a route to malignancy for more than half of all human cancers, 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. Malignant evolution enabled by p53 inactivation in mice proceeds through an ordered and predictable pattern of Trp53 loss of heterozygosity, accumulation of deletions, genome doubling and the emergence of gains and amplifications.
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