Cancers from Novel Pole -Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade

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 mutations P286R and S459F, which cause rapid albeit dis...

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Published inCancer research (Chicago, Ill.) Vol. 80; no. 24; pp. 5606 - 5618
Main Authors Galati, Melissa A, Hodel, Karl P, Gams, Miki S, Sudhaman, Sumedha, Bridge, Taylor, Zahurancik, Walter J, Ungerleider, Nathan A, Park, Vivian S, Ercan, Ayse B, Joksimovic, Lazar, Siddiqui, Iram, Siddaway, Robert, Edwards, Melissa, de Borja, Richard, Elshaer, Dana, Chung, Jiil, Forster, Victoria J, Nunes, Nuno M, Aronson, Melyssa, Wang, Xia, Ramdas, Jagadeesh, Seeley, Andrea, Sarosiek, Tomasz, Dunn, Gavin P, Byrd, Jonathan N, Mordechai, Oz, Durno, Carol, Martin, Alberto, Shlien, Adam, Bouffet, Eric, Suo, Zucai, Jackson, James G, Hawkins, Cynthia E, Guidos, Cynthia J, Pursell, Zachary F, Tabori, Uri
Format Journal Article
LanguageEnglish
Published United States 15.12.2020
Subjects
Animals
DNA Polymerase II - genetics
Humans
Immune Checkpoint Inhibitors
Mice
Mutation
Neoplasms - genetics
Poly-ADP-Ribose Binding Proteins - genetics
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Summary: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 mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation , independent of their exonuclease activity. Mouse and human correlates enabled novel stratification of 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, -driven cancers exhibited a continuous and stochastic mutagenesis mechanism, resulting in intertumoral and intratumoral heterogeneity. Checkpoint blockade did not prevent lymphomas, but rather likely promoted lymphomagenesis as observed in humans. These observations provide insights into the carcinogenesis of -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. .
Bibliography:Senior Authors; these authors contributed equally
Conceptualization: M.A.G., K.P.H., U.T., and Z.F.P.; Methodology: M.A.G., K.P.H., M.S.G., S.S., W.J.Z., Z.S., J.G.J., C.J.G., U.T., and Z.F.P.; Investigation: M.A.G., K.P.H., M.S.G., S.S., T.B., W.J.Z., V.S.P., A.B.E., L.J., I.S., R.d.B., and D.E.; Formal Analysis: M.A.G., K.P.H., M.S.G., W.J.Z., and C.J.G.; Resources and Data Curation: M.A.G., K.P.H., L.J., R.S., M.E., J.C., M.A., X.W., J.R., A.S., T.S. G.P.D., J.B., O.M., C.D., A.M., C.E.H., and C.J.G.; Writing – Original Draft: M.A.G., K.P.H., M.S.G., C.J.G., Z.F.P., and U.T.; Writing – Review & Editing: M.A.G., K.P.H., M.S.G., R.d.B., V.J.F., N.M.N., A.M., Z.S., J.G.J., C.J.G., Z.F.P., and U.T.; Visualization: M.A.G., K.P.H., M.S.G., V.S.P., and C.J.G.; Supervision: A.M., Z.S., C.E.H., C.J.G., Z.F.P., and U.T; Funding Acquisition: C.J.G., Z.S., Z.F.P., and U.T.
AUTHOR CONTRIBUTIONS
Current address: Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine, Irvine, CA, USA
These authors contributed equally
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-20-0624