Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade
| Autor: | Jonathan N. Byrd, James G. Jackson, Cynthia Hawkins, Alberto Martin, Uri Tabori, Walter J. Zahurancik, Dana Elshaer, Cynthia J. Guidos, Melissa Galati, Sumedha Sudhaman, Oz Mordechai, Ayse Bahar Ercan, Tomasz Sarosiek, Melyssa Aronson, Miki S. Gams, Victoria J. Forster, Taylor Bridge, Eric Bouffet, Andrea H. Seeley, Carol Durno, Melissa Edwards, Nathan Ungerleider, Vivian S. Park, Adam Shlien, Zachary F. Pursell, Lazar Joksimovic, Robert Siddaway, Nuno Miguel Nunes, Xia Wang, Zucai Suo, Iram Siddiqui, Jagadeesh Ramdas, Gavin P. Dunn, Jiil Chung, Richard de Borja, Karl P. Hodel |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Mechanism (biology) medicine.medical_treatment Mutant Mutagenesis (molecular biology technique) Cancer Immunotherapy Biology medicine.disease_cause medicine.disease Immune checkpoint 3. Good health Blockade 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis Cancer research medicine Carcinogenesis |
| Zdroj: | Cancer Research. 80:5606-5618 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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 three groups based on clinical phenotype and mutagenicity. Cancers driven by these mutations displayed striking resemblance to the human ultrahypermutation and specific signatures. Furthermore, Pole-driven cancers exhibited a continuous and stochastic mutagenesis mechanism, resulting in intertumoral 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 counseling, surveillance, and immunotherapy for patients. Significance: Two mouse models of polymerase exonuclease deficiency shed light on mechanisms of mutation accumulation and considerations for immunotherapy. See related commentary by Wisdom and Kirsch p. 5459 |
| Databáze: | OpenAIRE |
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