Epigenetic fingerprint in endometrial carcinogenesis: The hypothesis of a uterine field cancerization

Marina Di Domenico, Angela Santoro, Carmela Ricciardi, Mirella Iaccarino, Stefania Iaccarino, Mariagrazia Freda, Antonia Feola, Francesca Sanguedolce, Simona Losito, Daniela Pasquali, Attilio Di Spiezio Sardo, Giuseppe Bifulco, Carmine Nappi, Pantaleo Bufo, Maurizio Guida, Gaetano De Rosa, Alberto Abbruzzese, Michele Caraglia, Giuseppe Pannone

Research output: Contribution to journalArticle

Abstract

Transcriptional silencing by CpG island hypermethylation plays a critical role in endometrial carcinogenesis. In a collection of benign, premalignant and malignant endometrial lesions, a methylation profile of a complete gene panel, such steroid receptors (ERα, PR), DNA mismatch repair (hMLH1), tumor-suppressor genes (CDKN2A/P16 and CDH1/E-CADHE RIN) and WNT pathway inhibitors (SFRP1, SFRP2, SFRP4, SFRP5) was investigated in order to demonstrate their pathogenetic role in endometrial lesions. Our results indicate that gene hypermethylation may be an early event in endometrial endometrioid tumorigenesis. Particularly, ER?, PR, hMLH1, CDKN2A/P16, SFRP1, SFRP2 and SFRP5 revealed a promoter methylation status in endometrioid carcinoma, whereas SFRP4 showed demethylation in cancer. p53 immunostaining showed weak-focal protein expression level both in hyperplasic lesions and in endometrioid cancer. Non endometrioid cancers showed very low levels of epigenetic methylations, but strong p53 protein positivity. Fisher exact test revealed a statistically significant association between hMLH1, CDKN2A/P16 and SFRP1 genes methylation and endometrioid carcinomas and between hMLH1 gene methylation and peritumoral endometrium (p <0.05). Our data confirm that the methylation profile of the peritumoral endometrium is different from the altered molecular background of benign endometrial polyps and hyperplasias. Therefore, our findings suggest that the methylation of hMLH1, CDKN2A/P16 and SFRP1 may clearly distinguish between benign and malignant lesions. Finally, this study assessed that the use of an epigenetic fingerprint may improve the current diagnostic tools for a better clinical management of endometrial lesions.

Original languageEnglish
Pages (from-to)447-457
Number of pages11
JournalCancer Biology and Therapy
Volume12
Issue number5
DOIs
Publication statusPublished - Sep 1 2011

Keywords

  • E-cadherin
  • Endometrial lesions
  • hMLH1
  • Methylation specific PCR
  • p16
  • SFRP1
  • SFRP2
  • SFRP4
  • SFRP5
  • Wnt pathway

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

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  • Cite this

    Di Domenico, M., Santoro, A., Ricciardi, C., Iaccarino, M., Iaccarino, S., Freda, M., Feola, A., Sanguedolce, F., Losito, S., Pasquali, D., Di Spiezio Sardo, A., Bifulco, G., Nappi, C., Bufo, P., Guida, M., De Rosa, G., Abbruzzese, A., Caraglia, M., & Pannone, G. (2011). Epigenetic fingerprint in endometrial carcinogenesis: The hypothesis of a uterine field cancerization. Cancer Biology and Therapy, 12(5), 447-457. https://doi.org/10.4161/cbt.12.5.15963