Cancers from novel pole-mutant mouse models provide insights into polymerase-mediated hypermutagenesis and immune checkpoint blockade

Melissa A. Galati, Karl P. Hodel, Miki S. Gams, Sumedha Sudhaman, Taylor Bridge, Walter J. Zahurancik, Nathan A. Ungerleider, Vivian S. Park, Ayse B. Ercan, Lazar Joksimovic, Iram Siddiqui, Robert Siddaway, Melissa Edwards, Richard de Borja, Dana Elshaer, Jiil Chung, Victoria J. Forster, Nuno M. Nunes, Melyssa Aronson, Xia WangJagadeesh Ramdas, Andrea Seeley, Tomasz Sarosiek, Gavin P. Dunn, Jonathan N. Byrd, Oz Mordechai, Carol Durno, Alberto Martin, Adam Shlien, Eric Bouffet, Zucai Suo, James G. Jackson, Cynthia E. Hawkins, Cynthia J. Guidos, Zachary F. Pursell, Uri Tabori

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)5606-5618
Number of pages13
JournalCancer research
Volume80
Issue number24
DOIs
StatePublished - Dec 15 2020

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