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

Li, Hao-Dong; Lu, Changzheng; Zhang, He; Hu, Qing; Zhang, Junqiu; Cuevas, Ileana; Sahoo, Subhransu S.; Aguilar, Mitzi; Maurais, Elizabeth G; Zhang, Shanrong; Wang, Xiaojing; Akbay, Esra A.; Li, Guo Min; Li, Bo; Koduru, Prasad; Ly, Peter; Fu, Yang; Castrillón, Diego H.

doi:10.1172/jci.insight.138829

Cited by 32 publications

(30 citation statements)

References 66 publications

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“…Both strains were homozygous for MSH2 deletion and pol2 mutations, but the former was a MAT a / MAT a diploid—possibly originating from a whole-genome duplication event caused by failed cytokinesis ( 33 )—and the latter a MAT a / MAT alpha diploid—possibly originating from homothallic mating after a rare mating-type switch event ( Supplementary Figure S5A and B ). These results are in line with recent findings in yeast pol2-P301R cells ( 33 ) and in POLE P286R -driven mouse cancer models ( 42 ), and suggest that a transition to the diploid or polyploid state facilitates survival in the face of extreme mutagenesis as expected from the fact that deleterious mutations are frequently recessive and often masked in a heterozygotic diploid state. Similar to what was previously observed for cells carrying the strongest Pol ϵ hypermutators, we also found that both msh2Δ/msh2Δ pol2–4/pol2–4 and msh2Δ/msh2 pol2-L439V/pol2-L439V accumulated additional mutations in POL2 ( Supplementary Figure S3C and D ).…”

Section: Resultssupporting

confidence: 91%

Mutagenic mechanisms of cancer-associated DNA polymerase ϵ alleles

Herzog

Alonso-Pérez

Salguero

et al. 2021

Nucleic Acids Research

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A single amino acid residue change in the exonuclease domain of human DNA polymerase ϵ, P286R, is associated with the development of colorectal cancers, and has been shown to impart a mutator phenotype. The corresponding Pol ϵ allele in the yeast Saccharomyces cerevisiae (pol2-P301R), was found to drive greater mutagenesis than an entirely exonuclease-deficient Pol ϵ (pol2–4), an unexpected phenotype of ultra-mutagenesis. By studying the impact on mutation frequency, type, replication-strand bias, and sequence context, we show that ultra-mutagenesis is commonly observed in yeast cells carrying a range of cancer-associated Pol ϵ exonuclease domain alleles. Similarities between mutations generated by these alleles and those generated in pol2–4 cells indicate a shared mechanism of mutagenesis that yields a mutation pattern similar to cancer Signature 14. Comparison of POL2 ultra-mutator with pol2-M644G, a mutant in the polymerase domain decreasing Pol ϵ fidelity, revealed unexpected analogies in the sequence context and strand bias of mutations. Analysis of mutational patterns unique to exonuclease domain mutant cells suggests that backtracking of the polymerase, when the mismatched primer end cannot be accommodated in the proofreading domain, results in the observed insertions and T>A mutations in specific sequence contexts.

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Section: Resultssupporting

confidence: 91%

Mutagenic mechanisms of cancer-associated DNA polymerase ϵ alleles

Herzog

Alonso-Pérez

Salguero

et al. 2021

Nucleic Acids Research

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“…The human POLE-P286R mutation is found in the heterozygous condition, so we would not predict tumour cells carrying this mutation would necessarily show an S phase delay. Indeed mice heterozygous for the P286R are born healthy and fertile, with no enhancement of DNA damage markers although they are highly cancer prone [54]. In contrast, mice hemizygous for the POLE-P286R mutation generally show embryonic lethality.…”

Section: Discussionmentioning

confidence: 99%

Expression of the cancer-associatedDNA polymerase ε P286Rin fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication

Soriano

Vázquez

León

et al. 2021

Preprint

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Somatic mutations in the proofreading domain of the replicative DNA polymerase ϵ ( POLE- exonuclease domain mutations, POLE -EDMs) are frequently found in colorectal and endometrial cancers and, occasionally, in other tumours. POLE-associated cancers typically display hypermutation, microsatellite stability and a unique mutational signature, with a predominance of C > A transversions in the context TCT. To understand better the contribution of hypermutagenesis to tumour development, we have modelled the most recurrent POLE -EDM ( POLE-P286R ) in Schizosaccharomyces pombe . Whole-genome sequencing analysis revealed that the corresponding pol2-P287R allele also has a strong mutator effect in vivo, with a high frequency of base substitutions and relatively few frameshift mutations. The mutations are equally distributed across different genomic regions, but they occur within an AT-rich context. The most abundant base-pair changes are T C T > T A T transversions and, in contrast to human mutations, T C G > T T G transitions are not elevated, likely due to the absence of cytosine methylation in fission yeast. The pol2-P287R variant has an increased sensitivity to elevated dNTP levels and DNA damaging agents, and shows reduced viability on depletion of the Pfh1 helicase. In addition, S phase is aberrant and RPA foci are elevated, suggestive of persistent ssDNA or DNA damage, and the pol2-P287R mutation is synthetically lethal with rad3 inactivation , indicative of checkpoint activation. Significantly, deletion of genes encoding some translesion synthesis polymerases, most notably Pol κ, partially suppresses pol2-P287R hypermutation, indicating that polymerase switching contributes to this phenotype.

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“…6 The observation that TLS were relatively common among ECs with multiple classifying features may support this hypothesis because recent work in transgenic POLEmut mice suggested that co-occurring MMRd or TP53 mutations help POLEmut cancer cells to cope with a high mutational burden and may drive a higher neoantigen load. 20,21 However, the fact that we also observed TLS in p53abn and NSMP EC suggests that conditions favorable for TLS formation can also occur, though infrequently, in cancers with a relatively low mutational burden. Subsequent production of CXCL13 and in ammatory cytokines, chemokines and upregulation of cell adhesion molecules [22][23][24] including ICAM-2/3, VCAM-1 and MAdCAM-1 would mediate recruitment and adhesion of additional lymphocytes via high endothelial venules.…”

Section: Discussionmentioning

confidence: 72%

Tertiary lymphoid structures critical for prognosis in endometrial cancer patients - a TransPORTEC study

Horeweg

Workel

Loiero

et al. 2021

Preprint

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B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigated the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells showed presence of activated/memory B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis showed association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence showed L1CAM expression in mature TLS localized in the myometrial wall or at the tumor invasive border, independent of L1CAM expression the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank were evaluated. TLS were found in 19%, predominantly in mismatch-repair deficient and polymerase-epsilon mutant EC. Multivariable Cox regression analysis showed strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker.Statement of significance Tertiary lymphoid structures have a pivotal role in the immune response against endometrial cancer. Presence of mature tertiary lymphoid structures can be easily assessed using L1CAM immunohistochemistry and has independent favorable predictive value for recurrence and endometrial cancer-specific survival.

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

Cited by 32 publications

References 66 publications

Mutagenic mechanisms of cancer-associated DNA polymerase ϵ alleles

Mutagenic mechanisms of cancer-associated DNA polymerase ϵ alleles

Expression of the cancer-associatedDNA polymerase ε P286Rin fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication

Tertiary lymphoid structures critical for prognosis in endometrial cancer patients - a TransPORTEC study

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