@article{bafe458a11794d5686c69994b47ab9ab,
title = "Cancers from novel pole-mutant mouse models provide insights into polymerase-mediated hypermutagenesis and immune checkpoint blockade",
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.",
author = "Galati, {Melissa A.} and Hodel, {Karl P.} and Gams, {Miki S.} and Sumedha Sudhaman and Taylor Bridge and Zahurancik, {Walter J.} and Ungerleider, {Nathan A.} and Park, {Vivian S.} and Ercan, {Ayse B.} and Lazar Joksimovic and Iram Siddiqui and Robert Siddaway and Melissa Edwards and {de Borja}, Richard and Dana Elshaer and Jiil Chung and Forster, {Victoria J.} and Nunes, {Nuno M.} and Melyssa Aronson and Xia Wang and Jagadeesh Ramdas and Andrea Seeley and Tomasz Sarosiek and Dunn, {Gavin P.} and Byrd, {Jonathan N.} and Oz Mordechai and Carol Durno and Alberto Martin and Adam Shlien and Eric Bouffet and Zucai Suo and Jackson, {James G.} and Hawkins, {Cynthia E.} and Guidos, {Cynthia J.} and Pursell, {Zachary F.} and Uri Tabori",
note = "Funding Information: We thank Lauryl Nutter and Marina Gertsenstein (TCP Transgenic Core) and TCP staff for their scientific advice and technical support. The Tabori lab research is supported by a Stand Up To Cancer–Bristol-Myers Squibb Catalyst Research Grant (grant number: SU2C-AACR-CT-07-17). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research Grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. The Tabori lab is also supported by Meagan{\textquoteright}s Walk (MW-2014-10), b.r.a.i.n.child Canada, LivWise, a Canadian Institutes for Health Research (CIHR) Grant (PJT-156006), and the CIHR Joint Canada-Israel Health Research Program. The Pursell and Suo labs have been funded by the National Institute of Environmental Health Sciences (NIEHS) of the NIH under award number R01ES028271. The Pursell lab has also been funded by a Tulane University Carol Lavin-Bernick Faculty Grant. The Guidos lab acknowledges support from the Ontario Institute for Cancer Research, with funding from the Government and Ontario, as well as the Garron Family Cancer Center of the Hospital for Sick Children Research Institute. M.A. Galati is supported by the Government of Ontario, The Garron Family Cancer Centre, and the Peterborough K.M. Hunter Graduate Program. Funding Information: We thank Lauryl Nutter and Marina Gertsenstein (TCP Transgenic Core) and TCP staff for their scientific advice and technical support. The Tabori lab research is supported by a Stand Up To Cancer?Bristol-Myers Squibb Catalyst Research Grant (grant number: SU2C-AACR-CT-07-17). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research Grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. The Tabori lab is also supported by Meagan?s Walk (MW-2014-10), b.r.a.i.n.child Canada, LivWise, a Canadian Institutes for Health Research (CIHR) Grant (PJT-156006), and the CIHR Joint Canada-Israel Health Research Program. The Pursell and Suo labs have been funded by the National Institute of Environmental Health Sciences (NIEHS) of the NIH under award number R01ES028271. The Pursell lab has also been funded by a Tulane University Carol Lavin-Bernick Faculty Grant. The Guidos lab acknowledges support from the Ontario Institute for Cancer Research, with funding from the Government and Ontario, as well as the Garron Family Cancer Center of the Hospital for Sick Children Research Institute. M.A. Galati is supported by the Government of Ontario, The Garron Family Cancer Centre, and the Peterborough K.M. Hunter Graduate Program. Funding Information: grant for the conduct of a clinical trial) during the conduct of the study and grants from Roche (institutional grant for the conduct of a clinical trial) outside the submitted work. U. Tabori reports grants from Pediatric Stand Up 2 Cancer Catalyst (grant supported by Bristol Myers Squibb) during the conduct of the study. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = dec,
day = "15",
doi = "10.1158/0008-5472.CAN-20-0624",
language = "English",
volume = "80",
pages = "5606--5618",
journal = "Cancer Research",
issn = "0008-5472",
number = "24",
}