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.
Highlights
Pathogenic somatic mutations in the exonuclease domain of the replicative DNA polymerase Pol epsilon (POLE) define a subgroup of endometrial cancers (EC) with ultramutation, characteristic mutation signature (COSMIC signature 10) [1], enhanced immune response [2, 3] and excellent clinical outcome [4,5,6,7]
We examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, polymerase epsilon (POLE) variant frequency and the results from six in silico tools on 82 endometrial carcinoma (EC) with whole-exome sequencing from The Cancer Genome Atlas (TCGA)
Genomic characteristics of endometrial cancers with somatic POLE mutations in the complete TCGA cohort To elucidate which genomic alterations best define pathogenic somatic POLE mutations, we used data from 530 EC profiled by TCGA, including those reported in the 2013 publication [7]
Summary
Pathogenic somatic mutations in the exonuclease domain of the replicative DNA polymerase Pol epsilon (POLE) define a subgroup of endometrial cancers (EC) with ultramutation (frequently ≥100 mutations/Mb), characteristic mutation signature (COSMIC signature 10) [1], enhanced immune response [2, 3] and excellent clinical outcome [4,5,6,7]. For the five most common POLE mutations (P286R, V411L, S297F, A456P, and S459F) pathogenicity (in this sense meaning causal for tumour ultramutation) has been confirmed [4,5,6, 9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25], the classification of other, less frequent, POLE variants is currently challenging This is becoming an urgent problem, as POLE sequencing for molecular EC classification is rapidly entering clinical practice. We sought to provide pragmatic guidelines for the interpretation of POLE variants in cases analysed by targeted POLE sequencing where such comprehensive genomic data are unavailable, being mindful that the designation of a tumour as POLE-ultramutated EC may lead to withholding treatment, given the very favourable prognosis of this EC molecular subtype, so that a conservative approach to diagnosis is warranted
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