J Pathol Transl Med.  2020 Nov;54(6):471-479. 10.4132/jptm.2020.07.23.

The frequency of POLE-mutation in endometrial carcinoma and prognostic implications: a systemic review and meta-analysis

• Jumaah AS
• Salim MM
• Al-Haddad HS
• McAllister KA
• Yasseen AA

• KMID: 2509500
• DOI: http://doi.org/10.4132/jptm.2020.07.23

Abstract

Background
Endometrial carcinoma (EC) is classified into four distinct molecular subgroups including ultramutated DNA polymerase epsilon (POLE). POLE-mutated tumors have the best prognosis and are a promising target for immunotherapy. This meta-analysis consolidated the reported variation of POLE-mutant frequency and assessed prognostic value in EC.
Methods
Internet searches explored scientific data bases: EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials databases. Data was extracted from eligible studies including: sample size, number of positive POLE-mutant cases, sequencing information, clinicopathologic data, and survival data. Meta-analysis and a random-effects model produced pooled estimates of POLE frequency and prognostic parameters using 95% confidence intervals (CI), hazard ratios (HR), and odd ratios (OR).
Results
Six thousand three hundred and forty-six EC patient cases were pooled from 25 studies. The pooled proportion of POLE gene mutation in EC was 8.59% (95% CI, 7.01 to 10.32), of which 8.22% (95% CI, 6.27 to 10.42) were type I and 0.93% (95% CI, 0.34 to 1.81) type 2. Clinicopathologic data showed that POLE-mutated tumors are mostly endometrioid. They present at higher levels in earlier stages (I–II) of EC (89.51%; 95% CI, 81.11 to 95.66) at the highest grade III (51.53%; 95% CI, 36.08 to 66.84) with reduced myometrial invasion (OR, 1.48, 95% CI, 0.99 to 2.20). Survival analysis indicated favorable overall survival (HR, 0.90), disease-specific survival (HR, 0.41), and progression-free survival (HR, 0.23) for POLE mutant EC.
Conclusions
Almost one-tenth of EC patients have POLE-mutated tumors. Given their improved prognostic potential, identifying the POLE mutation status is key for the management of EC patients.

Keyword

Endometrial carcinoma; gene

Figure

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  Fig. 1. Flow chart of the studies identified, screened and included for final meta-analysis. A total of 1,252 studies met the eligibility criteria for inclusion, of which 26 were selected for final meta-analysis.

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  Fig. 2. Forest plot representation of the endometrial carcinoma (EC) patient cases for each study included for meta-analysis. POLE, DNA polymerase epsilon.

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  Fig. 3. Funnel plot for cases included for analysis. The visual assessment was symmetrical indicating no publication bias.

Reference

References

1. Bell DW, Ellenson LH. Molecular genetics of endometrial carcinoma. Annu Rev Pathol. 2019; 14:339–67.

2. Howlader N, Noone AM, Krapcho M, et al. SEER cancer statistics review, 1975-2011. Bethesda: National Cancer Institute;2014.

3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015; 65:5–29.

4. Spurdle AB, Bowman MA, Shamsani J, Kirk J. Endometrial cancer gene panels: clinical diagnostic vs research germline DNA testing. Mod Pathol. 2017; 30:1048–68.

5. Stelloo E, Nout RA, Naves LC, et al. High concordance of molecular tumor alterations between pre-operative curettage and hysterectomy specimens in patients with endometrial carcinoma. Gynecol Oncol. 2014; 133:197–204.

6. Hussein YR, Weigelt B, Levine DA, et al. Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations. Mod Pathol. 2015; 28:505–14.

7. Church DN, Stelloo E, Nout RA, et al. Prognostic significance of POLE proofreading mutations in endometrial cancer. J Natl Cancer Inst. 2015; 107:402.

8. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013; 497:67–73.

9. Auguste A, Genestie C, De Bruyn M, et al. Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers: a TransPORTEC initiative. Mod Pathol. 2018; 31:1851–61.

10. Talhouk A, McConechy MK, Leung S, et al. A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer. 2015; 113:299–310.

11. Stelloo E, Bosse T, Nout RA, et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer: a TransPORTEC initiative. Mod Pathol. 2015; 28:836–44.

12. Eggink FA, Van Gool IC, Leary A, et al. Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition. Oncoimmunology. 2017; 6:e1264565.

13. Bosse T, Nout RA, McAlpine JN, et al. Molecular classification of grade 3 endometrioid endometrial cancers identifies distinct prognostic subgroups. Am J Surg Pathol. 2018; 42:561–8.

14. Billingsley CC, Cohn DE, Mutch DG, Stephens JA, Suarez AA, Goodfellow PJ. Polymerase varepsilon (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing. Cancer. 2015; 121:386–94.

15. Le Gallo M, Rudd ML, Urick ME, et al. Somatic mutation profiles of clear cell endometrial tumors revealed by whole exome and targeted gene sequencing. Cancer. 2017; 123:3261–8.

16. Talhouk A, McConechy MK, Leung S, et al. Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer. Cancer. 2017; 123:802–13.

17. Rosa-Rosa JM, Leskela S, Cristobal-Lana E, et al. Molecular genetic heterogeneity in undifferentiated endometrial carcinomas. Mod Pathol. 2016; 29:1390–8.

18. Hoang LN, McConechy MK, Meng B, et al. Targeted mutation analysis of endometrial clear cell carcinoma. Histopathology. 2015; 66:664–74.

19. Abdulfatah E, Wakeling E, Sakr S, et al. Molecular classification of endometrial carcinoma applied to endometrial biopsy specimens: towards early personalized patient management. Gynecol Oncol. 2019; 154:467–74.

20. Stelloo E, Nout RA, Osse EM, et al. Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res. 2016; 22:4215–24.

21. Imboden S, Nastic D, Ghaderi M, et al. Phenotype of POLE-mutated endometrial cancer. PLoS One. 2019; 14:e0214318.

22. Billingsley CC, Cohn DE, Mutch DG, Hade EM, Goodfellow PJ. Prognostic significance of POLE exonuclease domain mutations in high-grade endometrioid endometrial cancer on survival and recurrence: a subanalysis. Int J Gynecol Cancer. 2016; 26:933–8.

23. Talhouk A, Hoang LN, McConechy MK, et al. Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: earlier prognostic information to guide treatment. Gynecol Oncol. 2016; 143:46–53.

24. Wong A, Kuick CH, Wong WL, et al. Mutation spectrum of POLE and POLD1 mutations in South East Asian women presenting with grade 3 endometrioid endometrial carcinomas. Gynecol Oncol. 2016; 141:113–20.

25. Wortman BG, Creutzberg CL, Putter H, et al. Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy. Br J Cancer. 2018; 119:1067–74.

26. Kommoss FK, Karnezis AN, Kommoss F, et al. L1CAM further stratifies endometrial carcinoma patients with no specific molecular risk profile. Br J Cancer. 2018; 119:480–6.

27. Karnezis AN, Leung S, Magrill J, et al. Evaluation of endometrial carcinoma prognostic immunohistochemistry markers in the context of molecular classification. J Pathol Clin Res. 2017; 3:279–93.

28. Espinosa I, Lee CH, D'Angelo E, Palacios J, Prat J. Undifferentiated and dedifferentiated endometrial carcinomas with POLE exonuclease domain mutations have a favorable prognosis. Am J Surg Pathol. 2017; 41:1121–8.

29. DeLair DF, Burke KA, Selenica P, et al. The genetic landscape of endometrial clear cell carcinomas. J Pathol. 2017; 243:230–41.

30. Meng B, Hoang LN, McIntyre JB, et al. POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium. Gynecol Oncol. 2014; 134:15–9.

31. Bellone S, Bignotti E, Lonardi S, et al. Polymerase epsilon (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro. Gynecol Oncol. 2017; 144:146–52.

32. Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015; 4:1.

33. MedCalc statistical software version 13.0.6 [Internet]. Ostend: MedCalc Software;2014. [cited 2020 Feb 27]. Available from: http://www.medcalc.org.

34. Jumaah AS, Al-Haddad HS, Mahdi LH, et al. Increased PTEN gene expression in patients with endometrial carcinoma from areas of high risk depleted uranium exposure. BMC Res Notes. 2019; 12:708.

35. van Gool IC, Eggink FA, Freeman-Mills L, et al. POLE proofreading mutations elicit an antitumor immune response in endometrial cancer. Clin Cancer Res. 2015; 21:3347–55.

36. Bakhsh S, Kinloch M, Hoang LN, et al. Histopathological features of endometrial carcinomas associated with POLE mutations: implications for decisions about adjuvant therapy. Histopathology. 2016; 68:916–24.

37. Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011; 343:d4002.