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Interpretation of somatic POLE mutations in endometrial carcinoma.
J Pathol. 2020 03; 250(3):323-335.JP

Abstract

Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours ('POLE-ultramutated') within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole-exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE-score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE-ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non-EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI-H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co-existent with MSI-H showed genomic alterations characteristic of POLE-ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI-H and a pathogenic POLE EDM had a 5-year recurrence-free survival (RFS) of 92.3%, comparable to previously reported POLE-ultramutated ECs. Additionally, 14 cases with non-pathogenic POLE EDM and MMRd/MSI-H had a 5-year RFS of 76.2%, similar to MMRd/MSI-H, POLE wild-type ECs, suggesting that these should be categorised as MMRd, rather than POLE-ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Authors+Show Affiliations

Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.Faculty of Medicine, University of British Columbia, Vancouver, Canada.Contextual Genomics Inc, Vancouver, Canada.Department of Gynaecology, Division of Gynaecologic Oncology, University of British Columbia and BC Cancer Agency, Vancouver, Canada.Department of Medical and Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands.Department of Women's Health, Tübingen University Hospital, Tübingen, Germany.Department of Women's Health, Tübingen University Hospital, Tübingen, Germany.Department of Oncology-Pathology, Karolinska Institutet, and Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.Department of Clinical Science and Education, Karolinska Institutet, and Department of Obstetrics and Gynaecology, Södersjukhuset, Stockholm, Sweden.Institute of Pathology, University of Bern, Bern, Switzerland.Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver General Hospital, Vancouver, Canada.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31829442

Citation

León-Castillo, Alicia, et al. "Interpretation of Somatic POLE Mutations in Endometrial Carcinoma." The Journal of Pathology, vol. 250, no. 3, 2020, pp. 323-335.
León-Castillo A, Britton H, McConechy MK, et al. Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol. 2020;250(3):323-335.
León-Castillo, A., Britton, H., McConechy, M. K., McAlpine, J. N., Nout, R., Kommoss, S., Brucker, S. Y., Carlson, J. W., Epstein, E., Rau, T. T., Bosse, T., Church, D. N., & Gilks, C. B. (2020). Interpretation of somatic POLE mutations in endometrial carcinoma. The Journal of Pathology, 250(3), 323-335. https://doi.org/10.1002/path.5372
León-Castillo A, et al. Interpretation of Somatic POLE Mutations in Endometrial Carcinoma. J Pathol. 2020;250(3):323-335. PubMed PMID: 31829442.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interpretation of somatic POLE mutations in endometrial carcinoma. AU - León-Castillo,Alicia, AU - Britton,Heidi, AU - McConechy,Melissa K, AU - McAlpine,Jessica N, AU - Nout,Remi, AU - Kommoss,Stefan, AU - Brucker,Sara Y, AU - Carlson,Joseph W, AU - Epstein,Elisabeth, AU - Rau,Tilman T, AU - Bosse,Tjalling, AU - Church,David N, AU - Gilks,C Blake, Y1 - 2020/01/29/ PY - 2019/07/07/received PY - 2019/10/25/revised PY - 2019/12/02/accepted PY - 2019/12/13/pubmed PY - 2020/7/8/medline PY - 2019/12/13/entrez KW - POLE KW - endometrial cancer KW - molecular classification SP - 323 EP - 335 JF - The Journal of pathology JO - J Pathol VL - 250 IS - 3 N2 - Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours ('POLE-ultramutated') within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole-exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE-score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE-ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non-EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI-H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co-existent with MSI-H showed genomic alterations characteristic of POLE-ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI-H and a pathogenic POLE EDM had a 5-year recurrence-free survival (RFS) of 92.3%, comparable to previously reported POLE-ultramutated ECs. Additionally, 14 cases with non-pathogenic POLE EDM and MMRd/MSI-H had a 5-year RFS of 76.2%, similar to MMRd/MSI-H, POLE wild-type ECs, suggesting that these should be categorised as MMRd, rather than POLE-ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. SN - 1096-9896 UR - https://www.unboundmedicine.com/medline/citation/31829442/Interpretation_of_somatic_POLE_mutations_in_endometrial_carcinoma_ L2 - https://doi.org/10.1002/path.5372 DB - PRIME DP - Unbound Medicine ER -