Role of Molecular Markers in Endometrial Cancer: Review

  • Santhosh KuriakoseEmail author
Original Article
Part of the following topical collections:
  1. Controversies to Consensus : Recent advances


Genomic studies have given insights into the heterogeneity of endometrial cancer based on its molecular alterations. The unravelling of a four-tier molecular classification of endometrial cancer, that is biologically different, has challenged clinicians to take up a therapeutic approach incorporating this vital information. Embracing this novel classification in a clinical setting is not always practical. This review looks into pragmatic methods to ascertain the molecular subtypes and how this can be incorporated into the traditional clinicopathological parameters. Integrated risk stratification will become an essential component of care in gynaecologic oncology. Molecular characterisation furthers accords an opportunity to identify and screen family members affected by Lynch syndrome. This review summarises the key features of the molecular subtype-based classification in endometrial carcinoma and the results published from various patient cohorts and also discusses the potential application of this information in a clinical setting that will result in delivering a more objective and individualised patient care.


Endometrial cancer Molecular marker The cancer genome atlas (TCGA) Mutation Diagnostic test 



This work was supported by the Science and Engineering Research Board grant (SERB/F/10827/2017–2018 dated 17 March 2018) accorded to Dr. Santhosh Kuriakose for the project ‘Genetic profiling of Carcinoma Endometrium and Prognostic significance of mutations in POLE gene’ conducted at Multidisciplinary Research Unit (MRU), DHR-ICMR-supported central research laboratory at Govt Medical College, Kozhikode (GMCK), Kerala, India. Author would like to thank Dr. Sathi P.P., Professor, Department of Pathology, Dr. Dhanasooraj Dhananjayan, Research Scientist II and Ms. Shammy S, Research Scientist I, MRU, GMCK.

Compliance with ethical standards

Conflict of interest

The author has no conflicts of interest to disclose.


  1. 1.
    Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10–7.CrossRefGoogle Scholar
  2. 2.
    Han G, Sidhu D, Duggan MA, Arseneau J, Cesari M, Clement PB, et al. Reproducibility of histological cell type in high-grade endometrial carcinoma. Mod Pathol. 2013;26(12):1594–604.CrossRefGoogle Scholar
  3. 3.
    Gilks C, Oliva E, Soslow R. Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma. Am J Surg Pathol. 2013;37(6):874–81.CrossRefGoogle Scholar
  4. 4.
    Levine DA. The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.CrossRefGoogle Scholar
  5. 5.
    van Gool IC, Eggink FA, Freeman-Mills L, Stelloo E, Marchi E, de Bruyn M, et al. POLE proofreading mutations elicit an antitumor immune response in endometrial cancer. Clin Cancer Res. 2015;21(14):3347–55.CrossRefGoogle Scholar
  6. 6.
    Garg K, Leitao M, Kauff N, Hansen J, Kosarin K, Shia J, et al. Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities. Am J Surg Pathol. 2009;33(6):925–33.CrossRefGoogle Scholar
  7. 7.
    Diaz-Padilla I, Romero N, Amir E, Matias-Guiu X, Vilar E, Muggia F, et al. Mismatch repair status and clinical outcome in endometrial cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2013;88(1):154–67.CrossRefGoogle Scholar
  8. 8.
    Imboden S, Nastic D, Ghaderi M, Rydberg F, Rau TT, Mueller MD, et al. Phenotype of POLE-mutated endometrial cancer. PLoS ONE. 2019;14(3):e0214318.CrossRefGoogle Scholar
  9. 9.
    Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96(4):261–8.CrossRefGoogle Scholar
  10. 10.
    Meyer LA, Broaddus RR, Lu KH. Endometrial cancer and Lynch syndrome: clinical and pathologic considerations. Cancer Control J Moffitt Cancer Cent. 2009;16(1):14–22.CrossRefGoogle Scholar
  11. 11.
    Stelloo E, Nout RA, Osse EM, Jürgenliemk-Schulz IJ, Jobsen JJ, Lutgens LC, 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(16):4215–24.CrossRefGoogle Scholar
  12. 12.
    McConechy MK, Talhouk A, Leung S, Chiu D, Yang W, Senz J, et al. Endometrial carcinomas with POLE exonuclease domain mutations have a favorable prognosis. Clin Cancer Res. 2016;22(12):2865–73.CrossRefGoogle Scholar
  13. 13.
    Yemelyanova A, Vang R, Kshirsagar M, Lu D, Marks MA, Shih IM, et al. Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis. Mod Pathol. 2011;24(9):1248–53.CrossRefGoogle Scholar
  14. 14.
    Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12(4):R41.CrossRefGoogle Scholar
  15. 15.
    Talhouk A, McConechy MK, Leung S, Li-Chang HH, Kwon JS, Melnyk N, et al. A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer. 2015;113(2):299–310.CrossRefGoogle Scholar
  16. 16.
    Köbel M, Piskorz AM, Lee S, Lui S, LePage C, Marass F, et al. Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma. J Pathol Clin Res. 2016;2(4):247–58.CrossRefGoogle Scholar
  17. 17.
    Cosgrove CM, Tritchler DL, Cohn DE, Mutch DG, Rush CM, Lankes HA, et al. An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer. Gynecol Oncol. 2018;148(1):174–80.CrossRefGoogle Scholar
  18. 18.
    Hussein YR, Weigelt B, Levine DA, Schoolmeester JK, Dao LN, Balzer BL, et al. Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations. Mod Pathol. 2015;28(4):505–14.CrossRefGoogle Scholar
  19. 19.
    Church DN, Stelloo E, Nout RA, Valtcheva N, Depreeuw J, ter Haar N, et al. Prognostic significance of POLE proofreading mutations in endometrial cancer. JNCI J Natl Cancer Inst. 2015;107(1):402.CrossRefGoogle Scholar
  20. 20.
    Stelloo E, Jansen AML, Osse EM, Nout RA, Creutzberg CL, Ruano D, et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann Oncol. 2017;28(1):96–102.PubMedGoogle Scholar
  21. 21.
    Salvesen HB, Haldorsen IS, Trovik J. Markers for individualised therapy in endometrial carcinoma. Lancet Oncol. 2012;13(8):e353–361.CrossRefGoogle Scholar
  22. 22.
    Bosse T, Nout RA, Stelloo E, Dreef E, Nijman HW, Jürgenliemk-Schulz IM, et al. L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early stage endometrial cancer: pooled PORTEC trial results. Eur J Cancer. 2014;50(15):2602–10.CrossRefGoogle Scholar
  23. 23.
    Zeimet AG, Reimer D, Huszar M, Winterhoff B, Puistola U, Abdel Azim S, et al. L1CAM in early-stage type I endometrial cancer: results of a large multicenter evaluation. JNCI J Natl Cancer Inst. 2013;105(15):1142–50.CrossRefGoogle Scholar
  24. 24.
    Liu Y, Patel L, Mills GB, Lu KH, Sood AK, Ding L, et al. Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma. J Natl Cancer Inst. 2014;106(9):dju245.CrossRefGoogle Scholar
  25. 25.
    McConechy MK, Talhouk A, Li-Chang HH, Leung S, Huntsman DG, Gilks CB, et al. Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas. Gynecol Oncol. 2015;137(2):306–10.CrossRefGoogle Scholar
  26. 26.
    Lancaster JM, Powell CB, Chen L, Richardson DL. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2015;136(1):3–7.CrossRefGoogle Scholar
  27. 27.
    PORTEC-4a: molecular profile-based versus standard adjuvant radiotherapy in endometrial cancer—full text view—
  28. 28.
    Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13.CrossRefGoogle Scholar

Copyright information

© Association of Gynecologic Oncologists of India 2019

Authors and Affiliations

  1. 1.Division of Gynaecologic Oncology, Department of Obstetrics and GynaecologyGovernment Medical CollegeKozhikodeIndia

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