Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade.
Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade.
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DOI：
10.1158/0008-5472.can-20-0624
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发表时间：
2020-12-15
期刊：
影响因子：
11.2
通讯作者：
Tabori U
中科院分区：
文献类型：
--
作者：
Galati MA;Hodel KP;Gams MS;Sudhaman S;Bridge T;Zahurancik WJ;Ungerleider NA;Park VS;Ercan AB;Joksimovic L;Siddiqui I;Siddaway R;Edwards M;de Borja R;Elshaer D;Chung J;Forster VJ;Nunes NM;Aronson M;Wang X;Ramdas J;Seeley A;Sarosiek T;Dunn GP;Byrd JN;Mordechai O;Durno C;Martin A;Shlien A;Bouffet E;Suo Z;Jackson JG;Hawkins CE;Guidos CJ;Pursell ZF;Tabori U
POLE突变是超突变型癌症的主要原因，但关于肿瘤发生机制、基因型-表型相关性和治疗考虑的问题仍然存在。在这项研究中，我们建立了携带癌症相关的POLE突变P286 R和S459 F的小鼠模型，这些突变导致体内癌症启动的快速但不同的时间，与它们的核酸外切酶活性无关。小鼠和人类相关性使得能够基于临床表型和致突变性将POLE突变新分层为3组。由这些突变驱动的癌症显示出与人类超超突变和特定特征的惊人相似之处。此外，极驱动的癌症表现出连续和随机的诱变机制，导致肿瘤间和肿瘤内的异质性。检查点阻断不能预防极淋巴瘤，但很可能促进淋巴瘤发生，如在人类中观察到的。这些观察结果为POLE驱动的肿瘤的致癌机制提供了见解，并为患者的遗传咨询，监测和免疫治疗提供了有价值的信息。
POLE mutations are a major cause of hypermutant cancers, yet questions remain regarding mechanisms of tumorigenesis, genotype-phenotype correlation, and therapeutic considerations. In this study, we establish mouse models harboring cancer-associated POLE mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation in vivo, independent of their exonuclease activity. Mouse and human correlates enabled novel stratification of POLE mutations into 3 groups based on clinical phenotype and mutagenicity. Cancers driven by these mutations displayed striking resemblance to the human ultra-hypermutation and specific signatures. Furthermore, Pole-driven cancers exhibited a continuous and stochastic mutagenesis mechanism, resulting in inter- and intratumoral heterogeneity. Checkpoint blockade did not prevent Pole lymphomas, but rather likely promoted lymphomagenesis as observed in humans. These observations provide insights into the carcinogenesis of POLE-driven tumors and valuable information for genetic counselling, surveillance, and immunotherapy for patients.