The clinicopathological characteristics of POLE-mutated/ultramutated endometrial carcinoma and prognostic value of POLE status: a meta-analysis based on 49 articles incorporating 12,120 patients
BMC Cancer volume 22, Article number: 1157 (2022)
This study was designed to investigate the frequency and clinicopathological characteristics of POLE-mutated/ultramutated (POLEmut) in endometrial carcinoma (EC) and assess the prognostic values of POLE status.
Electronic databases were screened to identify relevant studies. Meta-analysis was used to yield the pooled frequency of POLEmut and prognostic parameters by 95% confidence interval (CI), odd ratio (OR), and hazard ratio (HR).
Totally, 12,120 EC patients from 49 studies were included. The pooled frequency of POLEmut was 7.95% (95% CI: 6.52–9.51%) in EC, 7.95% (95% CI: 6.55–9.46%) in endometrioid endometrial carcinoma, and 4.45% (95% CI: 2.63–6.61%) in nonendometrioid endometrial carcinoma. A higher expression occurred in grade 3 (OR = 0.51, 95% CI: 0.36–0.73, P = 0.0002), FIGO stage I-II (OR = 1.91, 95% CI: 1.29–2.83, P = 0.0013), and myometrial invasion< 50% (OR = 0.66, 95% CI: 0.50–0.86, P = 0.0025). Survival analyses revealed favorable OS (HR = 0.68, 95% CI: 0.55–0.85, P = 0.0008), PFS (HR = 0.74, 95% CI: 0.59–0.93, P = 0.0085), DSS (HR = 0.61, 95% CI: 0.44–0.83, P = 0.0016), and RFS (HR = 0.47, 95% CI: 0.35–0.61, P < 0.0001) for POLEmut ECs. Additionally, the clinical outcomes of POLEmut group were the best, but those of p53-abnormal/mutated (p53abn) group were the worst, while those of microsatellite-instable (MSI)/hypermutated group and p53-wild-type (p53wt) group were medium.
The POLEmut emergered higher expression in ECs with grade 3, FIGO stage I-II, and myometrial invasion< 50%; it might serve as a highly favorable prognostic marker in EC; the clinical outcomes of POLEmut group were the best one among the four molecular subtypes.
Endometrial carcinoma (EC) is one of the most prevalent among gynecological cancer with a steady increase in incidence worldwide [1, 2]. Histotype and other clinicopathological parameters [such as Federation International of Gynecology and Obstetrics (FIGO) stage and tumor grade] are associated with the prognosis of ECs [3, 4]. However, both histotype and grade assignment are relatively poor reproducible [5,6,7], which leads to inaccurate findings within clinical trials, and over- or undertreatment of ECs.
In order to improve the clinical/pathology-based risk stratification system, the updated classification of EC identifies four subtype [polymerase-ε-mutated/ultramutated (POLEmut), microsatellite-instable (MSI)/hypermutated or mismatch repair-deficient (MMRd), p53-wild-type (p53wt), and p53-abnormal/mutated (p53abn)] according to The Cancer Genome Atlas (TCGA) and Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) based on various genetic and molecular features possesses a potential promise, proving to be reproducible, and demonstrating the associations with clinical outcomes [8,9,10,11].
POLE is involved in DNA replication and has recently been recognized as hereditary cancer-predisposing genes. The alterations of POLE are associated with occurrence, development and prognosis of tumors, especially in EC . The group of POLEmut, ECs with mutations in DNA POLE that is responsible for DNA replication and leads to exceedingly high somatic mutation frequencies (“ultramutated”: > 100 mutations per megabase) [13, 14], was found to be associated with markedly favorable outcomes, even with poor clinicopathological features [15, 16]. Additionally, they were also candidates for therapy of immune checkpoint inhibitor (ICIs) [17, 18].
However, a consensus has not been reached, with some studies advocating non-superior survival in POLEmut ECs [19, 20]; additionally, the frequency and specific clinicopathological features of POLEmut ECs were various in different studies. Therefore, it remains to be fully illuminated the histopathological features and prognostic of POLEmut ECs. Previous study had preliminarily explored the POLEmut ECs through meta-analysis , but it was based on limited histopathological features and prognostic parameters. Consequently, we made a comprehensive survey based on a large scale (49 articles incorporating 12,120 EC patients), multi-level (including eight subgroup analyses), and diverse dimensions (incorporating overall survival (OS), progression free survival (PFS), disease specific survival (DSS), and relapse free survival (RFS)) to summarize the pooled frequency and clinicopathological characteristics of POLEmut ECs and to assess the prognostic value.
Materials and methods
Data sources and literature searches
Studies were screened by a systematic electronic literature retrieval for abstracts of relevant studies in the published literature. PubMed, Cochrane Library, and EMBASE were searched and the data were updated as of December 30th, 2021. The basic search terms were used as follows: “endometrial carcinoma”, “endometrial cancer”, “POLE”, “polymerase epsilon”, and “Polymerase ɛ”. Full-text papers were scrutinized if abstracts did not provide substantial information. Moreover, the references of relevant articles were reviewed for additional studies. Data retrieval was completed in English.
Selection of studies and definition
Initially, two investigators performed a screening of titles and abstracts respectively, then examined the full-text of articles to acquire eligible studies. For the duplicate studies based on the same study patients, only the latest or most comprehensive data were included.
OS was defined as time from surgery until death of any cause; PFS was defined as time from surgery until there is evidence of progressive disease or if they died of the disease prior to the censoring date; DSS was defined as time from surgery until death due to EC; RFS was defined as time from surgery until there is evidence of recurrent disease.
(1) Prospective or retrospective studies to report the frequency and clinicopathological characteristics of POLEmut in EC; (2) the expression of POLE gene was reported using genetic testing (e.g. sequencing, sanger sequencing, next generation sequencing, and polymerase chain reaction); (3) a full paper had been published.
Data extraction was implemented conforming to the PRISMA guidance (Table S1). All eligible studies involved information as follows: the publication year and country, first author’s name, study type, and number of both ECs and POLEmut ECs.
The quality of included studies was assessed independently by two reviewers using the Newcastle-Ottawa Scale (NOS) for case-control and cohort studies, which encompassed the three dimensions of selection, comparability, and exposure, with a full score of 9 points.
The primary endpoint was to report the pooled frequency of POLEmut in ECs. Subgroup analyses were accomplished based on histotype, grade, FIGO stage, lymphovascular space invasion (LVSI), myometrial invasion, lymph node status, clinical risk stratification and adjuvant therapy. The measures to summarize them were odd ratios (ORs) and 95% confidence intervals (CIs). The second endpoint was to evaluate the prognostic value (including OS, PFS, DSS, and RFS) of POLEmut in ECs. The summary measures of survival analysis were hazard ratios (HRs) with corresponding 95% CIs. Funnel plots and Egger’s test were implemented to evaluate publication bias. Statistical analysis was performed through R 4.0 statistical software. Heterogeneity was assessed by I-square tests and chi-square. If P < 0.1 or I2 > 40%, remarkable heterogeneity existed. A random effect model was adopted to analysis the pooled data when heterogeneity existed, otherwise, a fixed effect model was employed.
Selection of study
Initially, 273 relevant articles were scrutinized intensively. Of them, 24 were filtered for duplication, and 104 were excluded for digression after screening the titles and abstracts. Then the full text of 145 articles was thoroughly reviewed, and 96 were filtered for: they were not human research, and not in English, commentaries, case reports, review articles, letters to the editor, and studies without enough data for calculation. Finally, a total of 49 articles (Table S2) incorporating 12,120 patients were included in this study. The elaborate procedure was displayed in Fig. 1.
Totally, 12,120 individuals in the 49 articles (50 cohorts) published until December 30th, 2021 were included. Studies were published from 2013 to 2021. The sample size ranged from 14 to 982. Of these studies, 8 were prospective, and 41 were retrospective. ORs and 95% CIs were used to report the frequency and clinicopathological characteristics of POLEmut in ECs, and HRs with corresponding 95% CIs were utilized to assess the value of POLEmut in clinical prognosis. Of all the adopted studies, 16 cohorts contained data for OS, 10 for PFS, 8 for DSS, and 8 for RFS. The principal characteristics were listed in Table 1.
The frequency of POLEmut in EC
A total of 49 articles containing 12,120 patients were included in the investigation of frequency of POLEmut ECs. The pooled frequency of POLEmut in ECs was 7.95% (95% CI: 6.52–9.51%) with significant heterogeneity among the studies (I2 = 86.3, 95% CI: 82.7–89.1%, P < 0.0001) (Fig. 2a). Furthermore, no publication bias was defined via Egger’s tests (z = 1.832, P = 0.06695) and funnel plot (Fig. 2b) in the pooled analysis.
We explored subgroup analyses based on histotype, grade, FIGO stage, LVSI, myometrial invasion, lymph node status, clinical risk stratification, and adjuvant therapy. The outcomes of specific subgroup analysis were shown in Table 2. The pooled ORs with 95% CIs were also calculated for POLEmut ECs according to each subgroup variable (Table 1).
Subgroup analysis was performed based on histotype. A total of 8412 patients with EEC from 32 cohorts were obtained for the meta-analysis. The pooled frequency of POLEmut in EECs was 7.95% (95% CI: 6.55–9.46%) with significant heterogeneity (I2 = 79.6, 95% CI: 71.8–85.2%, P < 0.0001). There were 1482 patients from 30 cohorts included for the NEEC meta-analysis. The POLEmut frequency in NEECs was 4.45% (95% CI: 2.63–6.61%) with significant heterogeneity (I2 = 56.0, 95% CI: 33.7–70.8%, P < 0.0001). The pooled OR of POLEmut EEC vs. NEEC was 1.35 (95% CI: 0.88–2.08, P = 0.1719) with heterogeneity (I2 = 49.6, 95% CI: 17.4–69.2%, P = 0.0047).
Subgroup analysis was accomplished based on grade. The pooled frequency of POLEmut ECs was 5.35% (95% CI: 4.16–6.67%) in grade 1–2 and 10.55% (95% CI: 8.35–12.94%) in grade 3. The pooled OR of POLEmut ECs with grade 1–2 vs. grade 3 was 0.51 (95% CI: 0.36–0.73, P = 0.0002).
Subgroup analysis was executed based on FIGO stage. The pooled frequency of POLEmut ECs was 9.15% (95% CI: 7.06–11.46%) in FIGO stage I-II and 2.89% (95% CI: 1.43–4.67%) in FIGO stage III-IV. The pooled OR of POLEmut ECs with FIGO stage I-II vs. FIGO stage III-IV was 1.91 (95% CI: 1.29–2.83, P = 0.0013).
Subgroup analysis was implemented based on LVSI. The pooled frequency of POLEmut ECs was 6.40% (95% CI: 3.82–9.48%) in LVSI present and 6.96% (95% CI: 5.32–8.77%) in LVSI absent.
Subgroup analysis was carried out based on myometrial invasion. The pooled frequency of POLEmut ECs was 4.78% (95% CI: 3.47–6.28%) in myometrial invasion ≥50 and 6.85% (95% CI: 5.04–8.89%) in myometrial invasion < 50%. The pooled OR of POLEmut ECs with myometrial invasion ≥50% vs. myometrial invasion < 50% was 0.66 (95% CI: 0.50–0.86, P = 0.0025).
Subgroup analysis was performed based on lymph node status. The pooled frequency of POLEmut ECs was 4.97% (95% CI: 0.55–12.07%) in lymph node status present and 9.46% (95% CI: 7.77–11.28%) in lymph node status absent.
Subgroup analysis was accomplished based on clinical risk stratification. The pooled frequency of POLEmut ECs was 5.87% (95% CI: 3.81–8.30%) in low-risk stratification, 7.18% (95%CI: 1.07–16.78%) in intermediate-risk stratification, and 8.87% (95% CI: 6.07–12.09%) in high-risk stratification.
Subgroup analysis was conducted based on with or without adjuvant therapy. The pooled frequency of POLEmut ECs was 9.00% (95% CI: 6.78–11.46%) with adjuvant therapy, and 6.27% (95% CI: 4.11–8.75%) without adjuvant therapy.
The frequency of other molecular subtypes (MSI and p53abn) in ECs
The pooled frequency of MSI in ECs was 27.23% (95% CI: 23.66–30.95%) (Fig. S1a) with significant heterogeneity among studies (I2 = 91.1, 95% CI: 88.6–93.0%, P < 0.0001) (Table S3); the pooled frequency of p53abn in ECs was 23.47% (95% CI: 19.70–27.46%) (Fig. S1b) with significant heterogeneity among studies (I2 = 90.8, 95% CI: 88.0–93.0%, P < 0.0001) (Table S3). No publication bias was calculated via Egger’s tests (Table S3) and funnel plot (Fig. S1c, d) in the pooled analyses.
Survival analyses were displayed by pooled HRs with 95% CIs for OS, PFS, DSS, and RFS. Of all the adopted studies, 16 cohorts contained data for OS, 10 for PFS, 8 for DSS, and 8 for RFS. The pooled HRs of POLEmut vs. POLE-wild-type (POLEwt) ECs were 0.68 (95% CI: 0.55–0.85, P = 0.0008) for OS (Fig. 3a), 0.74 (95% CI: 0.59–0.93, P = 0.0085) for PFS (Fig. 3b), 0.61 (95% CI: 0.44–0.83, P = 0.0016) for DSS (Fig. 3c), and 0.47 (95% CI: 0.35–0.61, P < 0.0001) for RFS (Fig. 3d). These results indicated benefit survival and favorable prognosis in POLEmut EC patients. No publication bias was calculated via funnel plot (Fig. S2) in the pooled analyses.
Additionally, univariable and multivariable analyses were pooled to test the associations among the four molecular subtypes (POLEmut, MSI, p53wt and p53abn) with clinical outcomes (OS, PFS, DSS and RFS) in ECs (Table 3). The results revealed that the clinical outcomes of POLEmut group were the best, but those of p53abn group were the worst, while those of MSI group and p53wt group were medium.
Assessment of study quality
All the studies were highly qualified (quality assessment of 49 included articles is summarized in Table S4) with relatively satisfying results for bias risk assessment.
Worldwide, EC is one of the most common cancers of women with survival rate not improving. TCGA research network firstly identified the molecular cohort of POLEmut EC that features a favorable prognostic potential, despite with bad clinicopathological parameters . Accumulating studies were conducted on the POLEmut, but the frequency and prognostic value of POLEmut in EC patients were variable among previous researches [3, 23,24,25]. Therefore, this study aimed to estimate the frequency and clinicopathological characteristics of POLEmut and the overall effect on prognosis of EC patients.
Our study revealed that 7.95% (95% CI: 6.52–9.51%) of EC patients harbored POLEmut. The results exhibited that there were no significant differences in histotype (EEC vs. NEEC) of POLEmut ECs; and no significant relations were observed between POLEmut and LVSI, lymph node status, clinical risk stratification, or adjuvant therapy. However, it should be noted that histotype and LVSI are features that generally subjective with interobserver variability and may not be reproducible between series [6, 26]. The vast majority of it presented higher expression at earlier stage and less myometrial invasion, both of which were “traditional” identified as an important marker of low-risk stratification; meanwhile, the POLEmut ECs presented at the highest grade (grade 3), which were generally considered to be associated with a higher risk of recurrence and death .
Studies have confirmed that POLEmut ECs had better clinical outcomes with survival analysis, even those at high grade [28,29,30]. Paradoxically, some investigators advocated that superior survival was not found in POLEmut ECs [19, 20]. Based on our study, EC patients with POLEmut possessed better clinical survivals (including OS, PFS, DSS, and RFS) than those with POLEwt. Additionally, according to both pooled univariable and multivariable analyses, the POLEmut cohort showed the best clinical prognosis among the four molecular subtypes, with a death risk of any cause lower than that of other three molecular subtypes, and a risk of recurrent/progressive disease lower; while the p53abn group, as expected, showed the worst prognosis. The reason why POLEmut correlates favorable outcomes in the patients remains unclear. Meng et al.  had speculated that this might due to the high mutation burden and the increase in base substitution; Howitt et al.  showed that POLEmut ECs were associated with high neoantigens and elevated CD8+ tumor infiltrating lymphocytes, which was counterbalanced by overexpression of program death-ligand. POLE proofreading mutations might elicit an anti-tumor response .
There is now an emerging link between high mutation burden in tumors and improved prognosis in cancer patients. Indeed, POLEmut tumors have been shown to feature higher immune infiltrations and programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression , which may offset the survival risk caused by higher tumor grades in ultramutated POLE and thus generate a favorable prognosis. Consequently, POLEmut in EC patients was a promising terapeutical target .
Talhouk et al.  found that half of POLEmut ECs were identified as with “high risk” based on stage, histology, and grade. It is clear that there may be both over-treatment and under-treatment of women based solely on application of the previous risk-assessment tool. In 2020, the European Society of Gynaecological Oncology (ESGO)/ European Society for Radiotherapy and Oncology (ESTRO)/ European Society of Pathology (ESP) published their joint guidelines for the management of EC, for the first time incorporating the TCGA findings [including groups of POLEmut, MMRd, p53abn and NSMP (surrogate of the copy number low/endometrioid group)] to assess the prognosis of EC in association with classic and distinct clinicopathologic prognostic factors (such as stage, grade, histotype, myometrial invasion or LVSI) in the risk stratification of EC . However, several points remain to be clarified, as the prognostic value of the TCGA molecular group may vary among diverse histotypes of EC . It has been recorded that POLEmut served as the molecular signature least affected by other prognostic clinicopathological factors . Furthermore, based on our study, there was no significant difference in frequency of POLEmut between EC patients with and without adjuvant therapy. For this reason, the clinical practice that many of the patients currently undergo adjuvant treatment may constitute an overtreatment. It is reasonable to identify POLEmut status at the moment of diagnosis and to mete out less intensive treatment for EC patients with POLEmut.
It remains obscure whether the favorable clinical outcomes observed in patients with POLEmut ECs were independent of the receipt of adjuvant therapy. Furthermore, other molecular factors and clinicopathological might have an independent prognostic value in the context of the TCGA classification , such as the LVSI . Therefore, novel initiatives stratifying ECs for clinical trials according to molecular subtype are recommended, since they will provide a key step toward precision medicine for ECs.
This study came across three drawbacks: firstly, there were only 8 prospective studies despite containing 49 articles involving 12,120 patients, for analyzing the clinicopathological characteristics of POLEmut ECs and prognostic value of POLE status; secondly, bias might exist to some extent for excluding relevant studies published in non-English language; the last was that the heterogeneity of included studies was high to some degree.
The POLEmut emergered higher expression in ECs with grade 3, FIGO stage I-II, and myometrial invasion< 50%; it might serve as a highly favorable prognostic marker in EC; the clinical outcomes of POLEmut group were the best one among the four molecular subtypes.
Availability of data and materials
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Immune Checkpoint Inhibitor
Endometrioid Endometrial Carcinoma
Nonendometrioid Endometrial Carcinoma
Progression Free Survival
Disease Specific Survival
Relapse Free Survival
Federation International of Gynecology and Obstetrics
Proactive Molecular Risk Classifier for Endometrial Cancer
Lymphovascular Space Invasion
European Society for Radiotherapy and Oncology
European Society of Pathology
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The list of the included studies.
Forest plot for the pooled frequency of (a) microsatellite-instable(MSI)/hypermutated and (b) p53-abnormal/mutated (p53abn) in endometrial carcinoma (EC); funnel plot for the pooled frequency of (c) MSI and (d) p53abn in EC.
The proportion of MSI and p53abn molecular subtypes in ECs.
Funnel plot of (a) overall survival (OS), (b) progression-free survival (PFS), (c) disease specific survival (DSS), and (d) relapse free survival (RFS) for POLEmut compared with POLEwt EC patients.
The Newcastle-Ottawa scale for quality assessment of the studies.
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Wu, Q., Zhang, N. & Xie, X. The clinicopathological characteristics of POLE-mutated/ultramutated endometrial carcinoma and prognostic value of POLE status: a meta-analysis based on 49 articles incorporating 12,120 patients. BMC Cancer 22, 1157 (2022). https://doi.org/10.1186/s12885-022-10267-2