MOLECULAR MARKERS OF ENDOMETRIAL CARCINOMA AND ASSOCIATED CLINICOPATHOLOGICAL FEATURES

DOI: https://doi.org/https://doi.org/10.29296/24999490-2022-03-05

E.I. Koroleva(1), A.A. Musaelyan(1, 2), V.D. Nazarov(1), S.V. Lapin(1), S.L. Vorobev(3), O.L. Sharova(3), E.S. Kozorezova(3), I.M. Korablina(3), V.L. Emanuel(1), S.V. Orlov(1, 2)
1-I.P. Pavlov First Saint-Petersburg State Medical University, Lva Tolstogo Str. 6–8, Saint Petersburg, 197022, Russian Federation;
2-Federal State Budget Research Institution "Research Institute of Medical Primatology",
Mira str. 177, Veseloe, Adler region, Sochi, Krasnodar krai, 354376, Russian Federation;
3-National Center for Clinical Morphological Diagnostics, Oleco Dundicha str., k. 2, 8, Saint Petersburg, 192283, Russian Federation

Introduction. In 2013 The Cancer Genome Atlas research group divided the molecular aberrations in endometrial cancer into four subtypes: POLE mutations, microsatellite instability, copy-number low and copy-number high. These subtypes have different prognosis and could probably mean different therapeutical options. The aim of the study. To estimate the prevalence of different molecular aberrations and to find out associated clinicopathological features. Methods. The study included 45 samples of endometrial carcinoma. Pathological structure and molecular features of each sample were evaluated. Immunohistochemical testing was used to find out the level of p53 expression. Genetic testing was carried out by PCR for MSI testing and by sequencing POLE exon 9 and exon 13 for point mitations. Results. Nor POLE mutations, nor abnormal p53 expression level were found in studied samples. The prevalence was 22% for MSI tumors. No significant difference in clinicopathological features was found between MSI and MSS tumors except for mitotic index that was higher in MSI tumors. Similarly, MSI tumors were less differentiated but the difference was not statistically significant. Conclusion. POLE mutations and abnormal p53 level are rare in low-grade endometrial carcinomas. Nevertheless, MSI tumors are common in this group and further research of their prognostic significance is important.
Keywords: 
endometrial cancer, molecular classification, POLE, MSI, p53

Список литературы: 
  1. McAlpine J., Leon-Castillo A., Bosse T. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses. J. Pathol. 2018; 244 (5): 538–49. https://doi.org/10.1002/path.5034
  2. Levine D., The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013; 497: 67–73. https://doi.org/10.1038/nature12113
  3. Stelloo E., Bosse T., Nout R.A., MacKay H.J., Church D.N., Nijman H.W., Leary A., Edmondson R.J., Powell M.E., Crosbie E.J., Kitchener H.C., Mileshkin L., Pollock P.M., Smit V.T., Creutzberg C.L. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod. Pathol. 2015; 28: 836–44. https://doi.org/10.1038/modpathol.2015.43
  4. Talhouk A., McConechy M.K., Leung S., Yang W., Lum A., Senz J., Boyd N., Pike J., Anglesio M., Kwon J.S., Karnezis A.N., Huntsman D.G., Gilks C.B., McAlpine J.N. Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer. 2017; 123 (5): 802–13. DOI: 10.1002/cncr.30496
  5. Imboden S., Nastic D., Ghaderi M., Rydberg F., Rau T.T., Mueller M.D., Epstein E., Carlson J.W. Phenotype of POLE-mutated endometrial cancer. PLoS ONE. 2019; 14 (3): e0214318. https://doi.org/10.1371/journal. pone.0214318
  6. Kanopiene D., Vidugiriene J., Valuckas K. P., Smailyte G., Uleckiene S., Bacher J. Endometrial cancer and microsatellite instability status. Open medicine. 2014; 10 (1): 70–6. https://doi.org/10.1515/med-2015-0005
  7. Hashmi A.A., Mudassir G., Hashmi R.N., Irfan M., Asif H., Khan E.Y., Abu Bakar S.M., Faridi N. Microsatellite Instability in Endometrial Carcinoma by Immunohistochemistry, Association with Clinical and Histopathologic Parameters. Asian Pac. J. Cancer Prev. 2019; 20 (9): 2601–6. https://doi.org/10.31557/APJCP.2019.20.9.2601.
  8. National Comprehensive Cancer Network Guidelines 3.2021 Uterine Neoplasms, 2021. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1473.
  9. Maxwell G.L., Risinger J.I., Alvarez A.A., Barrett J.C., Berchuck A. Favorable survival associated with microsatellite instability in endometrioid endometrial cancers. Obstet. Gynecol. 2001; 97 (3): 417–22. https://doi.org/10.1016/s0029-7844(00)01165-0.
  10. Murali R., Davidson B., Fadare O., Carlson J.A., Crum C.P., Gilks C.B., Irving J.A., Malpica A., Matias-Guiu X., McCluggage W.G., Mittal K., Oliva E., Parkash V., Rutgers J.K.L., Staats P.N., Stewart C.J.R., Tornos C., Soslow R.A. High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations. Int. J. Gynecol. Pathol. 2019; 38 (Iss 1 Suppl 1): 40–63. https://doi.org/10.1097/PGP.0000000000000491
  11. An H.J., Kim K.I., Kim J.Y., Shim J.Y., Kang H., Kim T.H., Kim J.K., Jeong J.K., Lee S.Y., Kim S.J. Microsatellite Instability in Endometrioid Type Endometrial Adenocarcinoma is Associated With Poor Prognostic Indicators. Am. J. Surg. Pathol. 2007; 31 (6): 846–53. https://doi.org/10.1097/01.pas.0000213423.30880.ac
  12. Yano M., Ito K., Yabuno A., Ogane N., Katoh T., Miyazawa M., Miyazawa M., Hasegawa K, Narahara H, Yasuda M. Impact of TP53 immunohistochemistry on the histological grading system for endometrial endometrioid carcinoma. Mod. Pathol. 2019; 32: 1023–31. https://doi.org/10.1038/s41379-019-0220-1
  13. Bell D. W., Ellenson L. H. Molecular Genetics of Endometrial Carcinoma. Annu. Rev. Pathol. 2017; 14 (1). https://doi.org/10.1146/annurev-pathol-020117-043609
  14. Schultheis A.M., Martelotto L.G., De Filippo M.R., Piscuglio S., Ng C.K., Hussein Y.R., Reis-Filho J.S., Soslow R.A., Weigelt B. TP53 Mutational Spectrum in Endometrioid and Serous Endometrial Cancers. Int. J. Gynecol. Pathol. 2016; 35 (4): 289–300. https://doi.org/10.1097/pgp.0000000000000243
  15. Luchini C., Bibeau F., Ligtenberg M.J.L., Singh N., Nottegar A., Bosse T., Miller R., Riaz N., Douillard J.Y., Andre F., Scarpa A. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann. Oncol. 2019; 30 (8): 1232–43. https://doi.org/10.1093/annonc/mdz116.
  16. McConechy M.K., Talhouk A., Leung S., Chiu D., Yang W., Senz J., Reha-Krantz L.J., Lee C.H., Huntsman D.G., Gilks C.B., McAlpine J.N. Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis. Clin. Cancer Res. 2016; 22 (12): 2865–73. https://doi.org/10.1158/1078-0432.CCR-15-2233.
  17. Buttin B.M., Powell M.A., Mutch D.G., Rader J.S., Herzog T.J., Gibb R.K., Huettner P., Edmonston T.B., Goodfellow P.J. Increased risk for hereditary nonpolyposis colorectal cancer-associated synchronous and metachronous malignancies in patients with microsatellite instability-positive endometrial carcinoma lacking MLH1 promoter methylation. Clin. Cancer Res. 2004; 10 (2): 481–90. https://doi.org/10.1158/1078-0432.ccr-1110-03.
  18. Steinbakk A., Malpica A., Slewa A., Gudlaugsson E., Janssen E.A., Arends M., Kruse A.J., Yinhua Y., Feng W., Baak J.P.. High frequency microsatellite instability has a prognostic value in endometrial endometrioid adenocarcinoma, but only in FIGO stage 1 cases. Anal. Cell Pathol. (Amst). 2010; 33 (5): 245–55. https://doi.org/10.3233/ACP-CLO-2010-0550
  19. Walsh M.D., Buchanan D.D., Cummings M.C., Pearson S.A., Arnold S.T., Clendenning M., Walters R., McKeone D.M., Spurdle A.B., Hopper J.L., Jenkins M.A., Phillips K.D., Suthers G.K., George J., Goldblatt J., Muir A., Tucker K., Pelzer E., Gattas M.R., Woodall S., Parry S., Macrae F.A., Haile R.W., Baron J.A., Potter J.D., Le Marchand L., Bapat B., Thibodeau S.N., Lindor N.M., McGuckin M.A., Young J.P. Lynch Syndrome-Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry. Clin. Cancer Res. 2010; 16 (7): 2214–24. https://doi.org/10.1158/1078-0432.ccr-09-3058
  20. Al Kushi A., Lim P., Aquino-Parsons C., Gilks C. B. Markers of Proliferative Activity Are Predictors of Patient Outcome for Low-Grade Endometrioid Adenocarcinoma But Not Papillary Serous Carcinoma of Endometrium. Mod. Pathol. 2002; 15 (4): 365–71. https://doi.org/10.1038/modpathol.3880531