TY - JOUR
T1 - Epigenetic fingerprint in endometrial carcinogenesis
T2 - The hypothesis of a uterine field cancerization
AU - Di Domenico, Marina
AU - Santoro, Angela
AU - Ricciardi, Carmela
AU - Iaccarino, Mirella
AU - Iaccarino, Stefania
AU - Freda, Mariagrazia
AU - Feola, Antonia
AU - Sanguedolce, Francesca
AU - Losito, Simona
AU - Pasquali, Daniela
AU - Di Spiezio Sardo, Attilio
AU - Bifulco, Giuseppe
AU - Nappi, Carmine
AU - Bufo, Pantaleo
AU - Guida, Maurizio
AU - De Rosa, Gaetano
AU - Abbruzzese, Alberto
AU - Caraglia, Michele
AU - Pannone, Giuseppe
PY - 2011/9/1
Y1 - 2011/9/1
N2 - 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.
AB - 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.
KW - E-cadherin
KW - Endometrial lesions
KW - hMLH1
KW - Methylation specific PCR
KW - p16
KW - SFRP1
KW - SFRP2
KW - SFRP4
KW - SFRP5
KW - Wnt pathway
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UR - http://www.scopus.com/inward/citedby.url?scp=80052364717&partnerID=8YFLogxK
U2 - 10.4161/cbt.12.5.15963
DO - 10.4161/cbt.12.5.15963
M3 - Article
C2 - 21709441
AN - SCOPUS:80052364717
VL - 12
SP - 447
EP - 457
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
SN - 1538-4047
IS - 5
ER -