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

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

doi:10.4161/cbt.12.5.15963

Cited by 37 publications

(25 citation statements)

References 57 publications

(51 reference statements)

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“…A few studies have evaluated the promoter methylation of CDH1/E-cadherin, a possible tumor-suppressor gene, in endometrial cancer (14,(46)(47)(48)(49). In the present study, we detected CpG promoter methylation of this gene in 31.4% of EEC samples, 21.1% of EHP cases and in 20.0% of cases with healthy endometrium.…”

Section: Rassf1a Gstp1 Cdh1supporting

confidence: 56%

“…Additionally, the recent data confirm that the methylation profile of the peritumoral endometrium is different from the altered molecular background of benign endometrial polyps and hyperplasias. Therefore, these findings suggest that the methylation of tumor-suppressor genes may clearly distinguish between benign and malignant lesions (14) which can be utilized in wide diagnostics or disease prevention. For example, RASSF1A promoter methylation in cervical cell smears can predict the presence of endometrial cancer with a 63.0% sensitivity and 96.3% specificity (56).…”

Section: Rassf1a Gstp1 Cdh1mentioning

confidence: 87%

“…methylation, histone deacetylation or miRNA expression) may underline the molecular biology of endometrial lesions (10,14). These changes are defined as heritable alterations in gene expression without alteration of the nucleotide sequence (15) and are the most common molecular alterations in human neoplasias (16).…”

Section: Introductionmentioning

confidence: 99%

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Promoter hypermethylation of the tumor-suppressor genes RASSF1A, GSTP1 and CDH1 in endometrial cancer

et al. 2013

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Abstract. Endometrial cancer is a common gynecological malignancy with a good prognosis in early stages of the disease. The CpG island in the promoter region of tumorsuppressor genes are frequently methylated in various types of human cancers. In the present study, we examined the methylation status of the GSTP1, CDH1 and RASSF1A genes in endometrioid endometrial cancer (EEC), endometrial complex hyperplasia (EHP) and healthy endometrium with the aim to identify correlations between promoter hypermethylation, disease risk and clinicopathological parameters. A nested two-stage methylation-specific PCR (MSP) was performed to analyze the promoter CpG methylation status of GSTP1, CDH1 and RASSF1A genes in the population studied. A total of 92 subjects were initially included in the study of which 41 EEC, 19 EHP and 20 controls were processed for final analyses. A significant difference was found between the study groups and the presence of promoter CpG hypermethylation status in the GSTP1 (P<0.05) and RASSF1A (P<0.0001) genes. RASSF1A, GSTP1 and CDH1 gene promoter methylation was present in 85.4, 68.3 and 31.4% of EEC samples when compared to that in the controls with 30.0, 35.0 and 20.0%, respectively. CpG methylation of all three investigated tumor-suppressor genes was found in 12.2% of EEC patients, in 4.2% of EHP patients and in 3.7% of the controls, respectively. Positive findings for the promoter methylation of two investigated genes were found in 48.7% of EEC patients, 26.0% of EHP patients and in 18.5% of the controls. With regard to histopathological variables and CpG methylation, we found significant correlations between the RASSF1A and GSTP1 genes and higher tumor grade, deeper myometrial invasion and positive metastatic involvement of pelvic lymph nodes. No associations were noted between promoter hypermethylation of the CDH1 gene and biological features of the endometrial cancer cases. The results indicate that aberrant CpG methylation of the promoter region in the GSTP1 and RASSF1A tumor-suppressor genes is an important event in carcinogenesis of endometrial cancer and may have an impact on tumor aggressiveness. Finally, the present study suggests that epigenetic alterations may be of diagnostic value for the better clinical management of premalignant endometrial lesions.

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Section: Rassf1a Gstp1 Cdh1supporting

confidence: 56%

Section: Rassf1a Gstp1 Cdh1mentioning

confidence: 87%

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Promoter hypermethylation of the tumor-suppressor genes RASSF1A, GSTP1 and CDH1 in endometrial cancer

et al. 2013

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“…In our study, we observed almost 80% of methylated carcinoma samples. Methylation of CDH1 (E-cadherin), another member of cadherin superfamily, is also important event in endometrial carcinogenesis 15 . Aberrant methylation in promoter region of CDH1 gene is associated with poor differentiation and myometrial invasion in endometrial carcinomas suggesting its possible role in tumor progression 16 .…”

Section: Discussionmentioning

confidence: 99%

Methylation analysis of tumor suppressor genes in endometroid carcinoma of endometrium using MS-MLPA

Dvořáková¹,

Chmelařová²,

Laco³

et al. 2013

BIOMED PAP

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Background. Epigenetic changes are considered to be a frequent event during tumor development. Hypermethylation of promoter CpG islands represents an alternative mechanism for inactivation of tumor suppressor genes, DNA repair genes, cell cycle regulators and transcription factors. The aim of this study was to investigate promoter methylation of specific genes in endometrial cancer by comparison with normal endometrial tissue. Materials and Methods. We used MS-MLPA (Methylation-specific Multiplex ligation-dependent probe amplification) to compare the methylation status of 59 tissue samples of endometroid type of endometrial carcinoma with 20 control samples of non-neoplastic endometrium. Results. Using 15% cut-off for methylation, we observed significantly higher methylation in the CDH13 gene in endometrial cancer group. We observed significantly higher methylation in both WT1 and GATA5 genes in IB stage of endometroid carcinoma. We also observed significantly higher methylation in GATA5 gene in the group of poorly differentiated endometroid carcinoma. Conclusion. The findings suggest the importance of hypermethylation of CDH13, WT1 and GATA5 genes in endometrial carcinogenesis and could have implications for future diagnostic and therapeutic strategies of endometrial cancer based on epigenetic changes.

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“…In previous reports, genetic mutations of oncogens such as p53, K-RAS and PTEN have been studied. However, recently it is known that epigenetic changes such as methylation, histon deacetylation, or micro RNA expressiorn can also affect the molecular biology of endometrial lesions on lining of the uterus (7,8). Epigenetics refer to heritable changes Copyright in gene activity and expression without changing the DNA sequence by pharmocological agents is dynamic and reversible.…”

Section: Intruductionmentioning

confidence: 99%

Promoter Hypermethylation Analysis of the Tumor Suppressor Genes RASSF1A and RASSF2A in Iranian Endometrial Carcinoma Patients

et al. 2017

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Introduction: The endometrial cancer (EC) is the seventh most common malignancies worldwide among females with good prognosis in early stages of the disease. The CpG Island in the promoter region of tumor-suppressor genes are frequently methylated in various types of human cancers. In the present study, we investigated the methylation pattern in promoter region of RASSF1A and RASSF2A genes in Endometrial cancer patients in Iranian women to identify correlations among promoter hypermethylation, disease risk and clinicopathological parameters. Methods: 28 patients and 22 healthy controls were studied. Isolation of genomic DNA from FFPE and peripheral blood was performed and Methylation-Specific PCR (MSP) was applied for analysis of the promoter CpG methylation status of RASSF1A and RASSF2A genes in the studied population. Results: A significant difference was found among the study groups and the presence of promoter CpG hypermethylation status in the RASSF1A (P = 0.0321) and RASSF2A (P = 0.0003) genes. RASSF1A, and RASSF2A gene promoter methylations were present in 53.57% and 42.85% of EC samples when compared to those in the controls with 31.81% and 9.09% respectively. Furthermore, methylation status between tissue and blood samples of RASSF1A, and RASSF2A genes was not significant (P = 0.49 and 0.09 respectively). Our results indicated a corollation between ages, menosososal state and tumor grade with RASSF1A, and RASSF2A promoter methylation. Conclusions: In our study, Hypermethylation of both RASSF1A and RASSF2A genes are important events in carcinogenesis of endometrial cancer. Epigenetic alternations may have diagnostic value for early diagnosis and better clicinal management of susceptibility to endometrial malignancies.

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

Cited by 37 publications

References 57 publications

Promoter hypermethylation of the tumor-suppressor genes RASSF1A, GSTP1 and CDH1 in endometrial cancer

Promoter hypermethylation of the tumor-suppressor genes RASSF1A, GSTP1 and CDH1 in endometrial cancer

Methylation analysis of tumor suppressor genes in endometroid carcinoma of endometrium using MS-MLPA

Promoter Hypermethylation Analysis of the Tumor Suppressor Genes RASSF1A and RASSF2A in Iranian Endometrial Carcinoma Patients

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