Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study

Domingo, Enric; Freeman-Mills, Luke; Rayner, Emily; Glaire, Mark A.; Briggs, Sarah; Vermeulen, Louis; Fessler, Evelyn; Medema, Jan Paul; Boot, Arnoud; Morreau, Hans; Wezel, Tom van; Liefers, G.J.; Lothe, Ragnhild; Danielsen, Stine A.; Sveen, Anita; Nesbakken, Arild; Zlobec, Inti; Lugli, Alessandro; Koelzer, Viktor H.; Berger, Martin D.; Castellví–Bel, Sergi; Muñoz, Jenifer; Bruyn, Marco de; Nijman, Hans W.; Novelli, Marco; Lawson, Kay; Oukrif, Dahmane; Frangou, Eleni; Dutton, Peter; Tejpar, Sabine; Delorenzi, Mauro; Kerr, Rachel; Kerr, David; Tomlinson, Ian; Church, David N.

doi:10.1016/s2468-1253(16)30014-0

Cited by 258 publications

(245 citation statements)

References 33 publications

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“…However, screening of 389 colorectal adenomas from 261 patients revealed three (0.8% adenomas; 1.1% patients) with somatic POLE mutations (Figure 1C), a frequency concordant with that found in colorectal cancers 11. Unfortunately, the limited amount of DNA available from these lesions precluded analysis of other driver mutations.…”

Section: Resultssupporting

confidence: 62%

“…POLE and POLD1 exonuclease domain mutations may occur in the germline, where they cause polymerase proofreading‐associated polyposis – a condition characterized by intestinal polyposis and tumours of the colorectum and uterus, among other organs 7. Somatic POLE exonuclease domain mutations (hereafter simply referred to as POLE mutations) occur in sporadic tumours of the endometrium (7–15% cases) 8, 9, colorectum (1–2%) 10, 11, and, less commonly, in other cancers (although, for reasons that are unclear, somatic POLD1 exonuclease domain mutations are very uncommon). 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.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 62%

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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“…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%

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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“…Recent data suggest similar findings in CRC with POLE mutations. Cox regression analysis on pooled data from three clinical trials and multiple patient cohorts detected 66 POLE mutations in 6,517 (1.0%) CRC samples [14]. POLE mutations were associated with young age, male sex, right‐sided tumor location, early disease stage, and absence of MMR deficiency.…”

Section: Molecular Tumor Boardmentioning

confidence: 99%

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

Castellucci

Goldstein

et al. 2017

The Oncologist

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Two cases of metastatic colorectal cancer with a POLE mutation, both of which were ultramutated and microsatellite stable, are presented and discussed from the standpoint of the basic biochemical mechanisms leading to a unique phenotype in POLE deficiency, the challenges faced with interpreting the genomic profiling of tumors in this important subset of patients, and the potential clinical implications.

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Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study

Abstract: Cancer Research UK, Academy of Medical Sciences, Health Foundation, EU, ERC, NIHR, Wellcome Trust, Dutch Cancer Society, Dutch Digestive Foundation.

Cited by 258 publications

References 33 publications

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

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

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

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

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