High frequency of <i>RASSF1A</i> and <i>RARb2</i> gene promoter methylation in morphologically normal endometrium adjacent to endometrioid adenocarcinoma

Arafa, Mohammad; Kridelka, Frédéric; Mathias, Valérie; Vanbellinghen, Jean-François; Renard, Isabelle; Foidart, Jean-Michel; Boniver, Jacques; Delvenne, Philippe

doi:10.1111/j.1365-2559.2008.03147.x

Cited by 40 publications

(38 citation statements)

References 30 publications

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“…As in our present study, RASSF1 was shown to be frequently methylated in EEC (Arafa et al 2008, Pallares et al 2008. However, where we found frequent methylation for RASSF1 in UPSC in line with Liao et al (2008) and Pallares et al (2008) found less RASSF1 methylation in UPSC (20%) than in EEC (61.5%).…”

Section: Discussioncontrasting

confidence: 47%

“…In view of the described differences in clinical, histological and molecular genetic characteristics of EEC and UPSC, we hypothesized that these differences also extend to methylation patterns. In EEC, methylation of MLH1 (Esteller et al 1999, Horowitz et al 2002, Kanaya et al 2003, RARb2 (Arafa et al 2008), RASSF1 (Arafa et al 2008) and CDKN2A (p16) (Guida et al 2009) has been suggested as early events in carcinogenesis. Many other epigenetically silenced genes have been described in EEC, such as MGMT (Furlan et al 2006), PTEN (Salvesen et al 2001, Macdonald et al 2004) and GSTP1 (Chan et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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Methylation profiles of endometrioid and serous endometrial cancers

Seeber

Zweemer

Marchionni³

et al. 2010

Endocrine-Related Cancer

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Promoter methylation is a gene-and cancer type-specific epigenetic event that plays an important role in tumour development. As endometrioid (endometrioid endometrial carcinoma, EEC) and serous endometrial cancers (uterine papillary serous carcinoma, UPSC) exhibit different clinical, histological and molecular genetic characteristics, we hypothesized that these differences may be reflected in epigenetic phenomena as well. Identification of a panel of methylation biomarkers could be helpful in a correct histological classification of these two subtypes, which solely on the basis of morphology is not always easy. Methylation-specific multiplex ligation-dependent probe amplification was used to assess the extent of promoter methylation of different tumour suppressor genes in EEC and UPSC. Methylation results were correlated with histology and survival. The median cumulative methylation index of all genes was significantly higher in EEC (124) than in UPSC (93) (P!0.001). Promoter methylation of CDH13 and MLH1 was more frequently present in EEC, while CDKN2B and TP73 were more frequently methylated in UPSC. Almost 90% of EEC and 70% of UPSC could be predicted by CDH13 and TP73. In EEC, methylation of MLH1 was associated with a shorter disease-free survival (DFS; P!0.0001) and overall survival (OS; PZ0.005). In a multivariate model, MLH1 methylation emerged as an additional prognostic factor to stage for DFS (PZ0.002). In conclusion, promoter methylation is more common in EEC than UPSC. A panel of methylation biomarkers could be useful to distinguish between the two histological subtypes of endometrial cancer. Furthermore, methylation of MLH1 may have prognostic value in EEC.

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Section: Discussioncontrasting

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Methylation profiles of endometrioid and serous endometrial cancers

Seeber

Zweemer

Marchionni³

et al. 2010

Endocrine-Related Cancer

View full text Add to dashboard Cite

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“…Other studies confirmed this finding: RASSF1A promoter region was reported to be methylated, in average 74% of cases of endometrial cancer patients which was associated with diseass progression (38). In a research conducted by Arafa et al it was observed that methylated promoter occurred in 74 % of patients and was corrolated with decreased gene expression level (39). It should be noted that aberrant methylation is associated with loss of heterozygosity (LOH) in chromosome 3p that frequently occur in endometrial cancer which is related with development, recurrence and survival of cancer and significantly associated with microsatellite instability in endometrial carcinomas that could block the increasing rate of genetic abnormalities in uterine carcinogenesis (40)(41)(42).…”

Section: Discussionsupporting

confidence: 65%

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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“…Pallarés et al (34) 74.0 --Pijnenborg et al (41) 85.0 --Seeber et al (40) 79.0 15.0 -Arafa et al (38) 74.0 --Liao et al (39) 61.5 --Kang et al (36) 81 cervical cancer. In contrast, common risk and predisposing epidemiological and histopathological factors associated with the development of uterine carcinomas have been identified.…”

Section: Rassf1a Gstp1 Cdh1mentioning

confidence: 99%

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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High frequency of RASSF1A and RARb2 gene promoter methylation in morphologically normal endometrium adjacent to endometrioid adenocarcinoma

Abstract: Promoter region methylation of RASSF1A and RARb2 genes is an early event in endometrial carcinogenesis.

Cited by 40 publications

References 30 publications

Methylation profiles of endometrioid and serous endometrial cancers

Methylation profiles of endometrioid and serous endometrial cancers

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

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

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