Regression of Chemotherapy-Resistant Polymerase ϵ (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab

Santin, Alessandro D.; Bellone, Stefania; Buza, Natália; Choi, Jungmin; Schwartz, Peter E.; Schlessinger, Joseph; Lifton, Richard P.

doi:10.1158/1078-0432.ccr-16-1031

Cited by 149 publications

(91 citation statements)

References 9 publications

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“…A significantly better survival has also been noted for POLE -mutant CRC [44]. Recent studies suggest this could be due to the high immunogenicity of the tumors [31,34,38,41,89,90], which likely results from the hypermutation increasing the number of neoepitopes that can be recognized by the immune system [37,40–42,44,92,93]. The improved survival suggests that, while the hypermutated POLE tumors are often of higher grade, they should be classified separately and could be treated less aggressively [36,94].…”

Section: Therapeutic Implications Of Dna Polymerase Deficiencymentioning

confidence: 99%

“…Other hypermutated tumors such as melanomas and lung cancers are also highly immunogenic [95,96]. Consequently, hypermutated tumors, including rare relapses of POLE -mutant EC, have responded well to immunotherapy [42,93,95– 97]. While further studies are needed, this may indicate that immunotherapy alone, if necessary, could replace radiation and chemotherapy after surgery in these cases.…”

Section: Therapeutic Implications Of Dna Polymerase Deficiencymentioning

confidence: 99%

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Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Barbari

Shcherbakova

2017

DNA Repair

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The fidelity of DNA replication relies on three error avoidance mechanisms acting in series: nucleotide selectivity of replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). MMR defects are well known to be associated with increased cancer incidence. Due to advances in DNA sequencing technologies, the past several years have witnessed a long-predicted discovery of replicative DNA polymerase defects in sporadic and hereditary human cancers. The polymerase mutations preferentially affect conserved amino acid residues in the exonuclease domain and occur in tumors with an extremely high mutation load. Thus, a concept has formed that defective proofreading of replication errors triggers the development of these tumors. Recent studies of the most common DNA polymerase variants, however, suggested that their pathogenicity may be determined by functional alterations other than loss of proofreading. In this review, we summarize our current understanding of the consequences of DNA polymerase mutations in cancers and the mechanisms of their mutator effects. We also discuss likely explanations for a high recurrence of some but not other polymerase variants and new ideas for therapeutic interventions emerging from the mechanistic studies.

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Section: Therapeutic Implications Of Dna Polymerase Deficiencymentioning

confidence: 99%

Section: Therapeutic Implications Of Dna Polymerase Deficiencymentioning

confidence: 99%

Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Barbari

Shcherbakova

2017

DNA Repair

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“…Second, understanding early drivers of hypermutation may be useful for predicting the cancer's evolutionary trajectory and accumulation of additional mutations. Finally, hypermutation is correlated with response to immune checkpoint inhibitors, which can lead to durable remissions in some patients (Bouffet et al, 2016; Johanns et al, 2016; Le et al, 2015; Rizvi et al, 2015; Santin et al, 2016; Van Allen et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Hypermutation in Human Cancer

Campbell¹,

Light²,

Fabrizio³

et al. 2017

Cell

664

662

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Summary We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.

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“…POLE ‐mutant colorectal and endometrial cancers have an excellent prognosis 8, 11, 12, 13, probably owing to a robust antitumour immune response against the multitude of immunogenic neoantigens that they are predicted to harbour 11, 14, 15. Very recent reports have also suggested that these tumours may be highly responsive to immune checkpoint inhibition 16.…”

Section: Introductionmentioning

confidence: 99%

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

Temko

Gool

Rayner

et al. 2018

The Journal of Pathology

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Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate, and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown. Here, we have shown that pathogenic POLE mutations are detectable in non‐malignant precursors of endometrial and colorectal cancer. Using genome and exome sequencing, we found that multiple driver mutations in POLE‐mutant cancers show the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumourigenesis. In POLE‐mutant cancers, the proportion of monoclonal predicted neoantigens was similar to that in other cancers, but the absolute number was much greater. We also found that the prominent CD8+ T‐cell infiltrate present in POLE‐mutant cancers was evident in their precursor lesions. Collectively, these data indicate that somatic POLE mutations are early, quite possibly initiating, events in the endometrial and colorectal cancers in which they occur. The resulting early onset of genomic instability may account for the striking immune response and excellent prognosis of these tumours, as well as their early presentation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Regression of Chemotherapy-Resistant Polymerase ϵ (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab

Cited by 149 publications

References 9 publications

Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Comprehensive Analysis of Hypermutation in Human Cancer

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

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