The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
Interpretation of somatic POLE mutations in endometrial carcinoma
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194
Signatures of mutational processes in human cancer
Initiative, A. P. C. G., Alexandrov, L. B., ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, PedBrain, I., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. V., et al. (2013) · Nature · doi:10.1038/nature12477 · Cited by 9,660
Kumar, P., Henikoff, S., & Ng, P. C. (2009) · Nature Protocols · doi:10.1038/nprot.2009.86 · Cited by 6,521
Integrated genomic characterization of endometrial carcinoma
The Cancer Genome Atlas Research Network, & Levine, D. A. (2013) · Nature · doi:10.1038/nature12113 · Cited by 5,784
Umar, A., Boland, C. R., Terdiman, J. P., Syngal, S., Chapelle, A. D. L., Ruschoff, J., Fishel, R., Lindor, N. M., Burgart, L. J., Hamelin, R., et al. (2004) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djh034 · Cited by 3,183
REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants
Ioannidis, N. M., Rothstein, J. H., Pejaver, V., Middha, S., McDonnell, S. K., Baheti, S., Musolf, A., Li, Q., Holzinger, E., Karyadi, D., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.08.016 · Cited by 2,908
Predicting the Functional Effect of Amino Acid Substitutions and Indels
Choi, Y., Sims, G. E., Murphy, S., Miller, J. R., & Chan, A. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046688 · Cited by 2,890
Landon, M., Saam, J., Brown, K. L., Moyes, K., Evans, B., & Wenstrup, R. (2015) · Oncology · doi:10.1159/000430097 · Cited by 1,939
Saam, J., Arnell, C., Theisen, A., Moyes, K., Marino, I., Roundy, K. M., & Wenstrup, R. J. (2015) · Oncology · doi:10.1159/000437307 · Cited by 1,526
The CORGI Consortium, Palles, C., The WGS500 Consortium, Cazier, J.-B., Howarth, K. M., Domingo, E., Jones, A. M., Broderick, P., Kemp, Z., Spain, S. L., et al. (2013) · Nature Genetics · doi:10.1038/ng.2503 · Cited by 997
Cited by
ESGO/ESTRO/ESP Guidelines for the Management of Patients with Endometrial Carcinoma
Concin, N., Matias-Guiu, X., Vergote, I., Cibula, D., Mirza, M. R., Marnitz, S., Ledermann, J., Bosse, T., Chargari, C., Fagotti, A., et al. (2021) · International Journal of Gynecological Cancer · doi:10.1136/ijgc-2020-002230 · Cited by 1,989
Self-citationLeón-Castillo, A., de Boer, S. M., Powell, M. E., Mileshkin, L. R., Mackay, H. J., Leary, A., Nijman, H. W., Singh, N., Pollock, P. M., Bessette, P., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.20.00549 · Cited by 855
Self-citationSingh, N., Piskorz, A. M., Bosse, T., Jimenez‐Linan, M., Rous, B., Brenton, J. D., Gilks, C. B., & Köbel, M. (2020) · The Journal of Pathology · doi:10.1002/path.5375 · Cited by 316
Self-citationShah, S. M., Demidova, E. V., Ringenbach, S., Faezov, B., Andrake, M., Gandhi, A., Mur, P., Viana-Errasti, J., Xiu, J., Swensen, J., et al. (2024) · Cancer Research Communications · doi:10.1158/2767-9764.crc-23-0312 · Cited by 16
Metadata
- Authors
- 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.
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2020-01-29
- Volume
- 250
- Issue
- 3
- Pages
- 323-335
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- OpenAlex
- W2996314623
- Cited by
- 409
- References
- 43
- FWCI
- 28.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
