A PoleP286R mouse model of endometrial cancer recapitulates high mutational burden and immunotherapy response.

JCI Insight
Hao-Dong LiDiego H Castrillon

Abstract

Cancer is instigated by mutator phenotypes, including deficient mismatch repair and p53-associated chromosomal instability. More recently, a distinct class of cancers was identified with unusually high mutational loads due to heterozygous amino acid substitutions (most commonly P286R) in the proofreading domain of DNA polymerase ε, the leading strand replicase encoded by POLE. Immunotherapy has revolutionized cancer treatment, but new model systems are needed to recapitulate high mutational burdens characterizing human cancers and permit study of mechanisms underlying clinical responses. Here, we show that activation of a conditional LSL-PoleP286R allele in endometrium is sufficient to elicit in all animals endometrial cancers closely resembling their human counterparts, including very high mutational burden. Diverse investigations uncovered potentially novel aspects of Pole-driven tumorigenesis, including secondary p53 mutations associated with tetraploidy, and cooperation with defective mismatch repair through inactivation of Msh2. Most significantly, there were robust antitumor immune responses with increased T cell infiltrates, accelerated tumor growth following T cell depletion, and unfailing clinical regression following ...Continue Reading

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Citations

Dec 17, 2020·Cancer Research·Amy J Wisdom, David G Kirsch
Mar 26, 2021·Nucleic Acids Research·Mareike HerzogFabio Puddu

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Datasets Mentioned

BETA
PRJNA613918

Methods Mentioned

BETA
dissection
electrophoresis
PCR
flow cytometry

Software Mentioned

Picard
SnpEff
BWA
samtools
ImageJ
NetMHC
Isis
PCAWG
GraphPad Prism
GATK

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