DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study

Tao, Meng Hua; Shields, Peter G.; Nie, Jing; Millen, Amy E.; Ambrosone, Christine B.; Edge, Stephen B.; Krishnan, Shiva; Marian, Cătălin; Xie, Bingteng; Winston, Janet S.; Vito, Dominica; Trevisan, Maurizio; Freudenheim, Jo L.

doi:10.1007/s10549-008-0028-z

Cited by 42 publications

(65 citation statements)

References 30 publications

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“…In our study, the prevalence of CDH1 methylation was also significantly associated with tumor histological grade, thus indicating that this event occurs at a later stage and promotes the progression to higher histological grades. Therefore, our finding is in agreement with earlier studies, which reported associations between CpG island methylation and poor histological differentiation of breast tumors (Nass et al, 2000;Raish et al, 2009;Tao et al, 2009;Shargh et al, 2011). CDH1 gene hypermethylation was also found significantly associated with lymph node metastasis suggesting that the breast tumors with CDH1 CpG-island hypermethylation may possess a biologically aggressive phenotype, as suggested in previous study (Shinozaki et al, 2005).…”

Section: Discussionsupporting

confidence: 94%

Loss of Expression and Aberrant Methylation of the CDH1 (E-cadherin) Gene in Breast Cancer Patients from Kashmir

Asiaf

Ahmad²,

Aziz³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Aberrant promoter hypermethylation has been recognized in human breast carcinogenesis as a frequent molecular alteration associated with the loss of expression of a number of key regulatory genes and may serve as a biomarker. The E-cadherin gene (CDH1), mapping at chromosome 16q22, is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. The aim of our study was to assess the methylation pattern of CDH1 and to correlate it with the expression of E-cadherin, clinicopathological parameters and hormone receptor status in breast cancer patients of Kashmir. Materials and Methods: Methylation specific PCR (MSP) was used to determine the methylation status of CDH1 in 128 invasive ductal carcinomas (IDCs) paired with the corresponding normal tissue samples. Immunohistochemistry was used to study the expression of E-cadherin, ER and PR. Results: CDH1 hypermethylation was detected in 57.8% of cases and 14.8% of normal adjacent controls. Reduced levels of E-cadherin protein were observed in 71.9% of our samples. Loss of E-cadherin expression was significantly associated with the CDH1 promoter region methylation (p<0.05, OR=3.48, CI: 1.55-7.79). Hypermethylation of CDH1 was significantly associated with age at diagnosis (p=0.030), tumor size (p=0.008), tumor grade (p= 0.024) and rate of node positivity or metastasis (p=0.043). Conclusions: Our preliminary findings suggest that abnormal CDH1 methylation occurs in high frequencies in infiltrating breast cancers associated with a decrease in E-cadherin expression. We found significant differences in tumor-related CDH1 gene methylation patterns relevant to tumor grade, tumor size, nodal involvement and age at diagnosis of breast tumors, which could be extended in future to provide diagnostic and prognostic information.

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Section: Discussionsupporting

confidence: 94%

Loss of Expression and Aberrant Methylation of the CDH1 (E-cadherin) Gene in Breast Cancer Patients from Kashmir

Asiaf

Ahmad²,

Aziz³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…This demonstrates that a careful screen for reliable reference genes is indispensable for each individual experimental situation. The frequency of P16 methylation in breast cancer ranged from 14-37.5% [16][17][18]. In this study, P16 gene promoter was found 24.2% hypermethylated in patients with sporadic breast cancer.…”

Section: Discussionmentioning

confidence: 48%

Promoter methylation and expression changes of CDH1 and P16 genes in invasive breast cancer and adjacent normal breast tissue

Çavuşoğlu¹,

Sevinç²,

Saydam³

et al. 2010

neo

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We studied the promoter methylation status and expression levels of P16 and CDH1 genes in breast cancer and their adjacent normal tissues with normal control breast tissues, to correlate with their histopathological parameters. Hundred twenty four samples (tumor and adjacent nonmalignant tissues) from 62 breast cancer patients and 4 normal control breast tissues were included in the study. We used methylation specific PCR to evaluate methylation status and quantitative RT-PCR to measure the gene expression levels. Methylation incidence of P16 gene and CDH1 gene in tumor tissues were 24.2 % and 33.9 %, respectively. CDH1 and P16 gene were not methylated in normal control tissues. CDH1 underexpression is found to be significant in correlation with advanced stage, histologic type, high tumor grade and lymph node involvement. P16 expression is found not to be significantly related with any histopathological parameters. But 60% of cases which overexpresses P16 were estrogen negative, and 40% of them were histologic grade 3. Both P16 and CDH1 had different expression levels in tumor tissues compared to the adjacent normal tissues and in adjacent normal tissues compared to the normal non-tumor tissues. Key words: Breast cancer, P16, CDH1, methylationhomophilic cell-cell adhesion in epithelial tissues. CDH1 (E Cadherin), a Ca++ dependent transmembrane glycoprotein functioning in cell to cell adhesion placed in 16q22.1, is one of the cardinal regulators of morphogenesis [7]. Decreased levels of CDH1 expression related with the advanced stage and poorly differentiated cancers [8].We aimed to find out any possible relationship and concordance between promoter methylation status and expression levels of CDH1 and P16 genes, two critical genes in the carcinogenesis, with the histopathological parameters in sporadic breast cancer and adjacent normal breast tissue. Materials and methodsBreast cancer primary tissues. Breast tumors and adjacent nonmalignant tissues from resection margin are obtained from the Dokuz Eylül Breast Tumor Biobank (DEBTB) under permission of local clinical and laboratory research ethical council for analysis of patient samples. All the breast tissue samples were collected from patients, who had neither chemotherapy nor radiotherapy before operation. Tissue samples were constituted of tumor cells at average of 60% of the whole specimens Changes in the status of DNA methylation represent one of the most common molecular alterations in human neoplasia [1], including breast cancer [2]. Methylation in breast cancer has been related to clinical and pathologic characteristics evident at presentation and clinical outcomes. A higher prevalence of HIN-1 and RAR β2 methylation was found in the lymph nodes, bone, brain, and lung metastases than the primary tumor [3]. Widschwendter and colleagues [4] reported that the methylation of certain genes was associated with hormone receptor status, in addition to the response to treatment with tamoxifen.An uncontrolled cell division requires further progression through G1 p...

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“…Detailed study methods have been published previously (5,34). In brief, the Western New York Exposures and Breast Cancer Study included 1170 women with primary, histologically confirmed, incident breast cancer who were aged 35-79 y at diagnosis and 2115 randomly selected population control subjects who were frequencymatched to cases for age and race.…”

Section: Subjects and Study Designmentioning

confidence: 99%

“…ER and PR status were determined by using immunohistochemistry at the Georgetown University Lombardi Comprehensive Cancer Center, and stained tumor slides were evaluated by a single certified pathologist as previously described (34).…”

Section: Subjects and Study Designmentioning

confidence: 99%

“…In addition, the inactivation of other tumor suppressor genes involved in cell adhesion (E-cadherin), hormone, and receptor-mediated cell signaling (ie, RAR-b 2 ) by promoter methylation is a critical event in breast carcinogenesis (22). The promoter methylation of E-cadherin, p16, and RAR-b 2 has also been shown to occur more frequently in breast cancer cell lines and breast tumors than in nonmalignant adjacent breast tissue or benign breast tissue from cancer patients (25)(26)(27)(28)(29)(30)(31)(32) and is associated with clinical features of breast cancer, including distant metastasis and ER-positive tumors (32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

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Body mass and DNA promoter methylation in breast tumors in the Western New York Exposures and Breast Cancer Study

Tao¹,

Marian²,

Nie³

et al. 2011

The American Journal of Clinical Nutrition

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Background: The mechanism of the observed association between body mass, particularly centralized body fat, and postmenopausal breast cancer risk is not well understood. Objective: We hypothesized that body mass may affect DNA methylation through increased estrogen and chronic inflammation. The association between body mass and promoter methylation in breast tumors was investigated in a population-based, case-control study. Design: The promoter methylation of E-cadherin, p16, and RAR-b 2 genes was assessed in breast tumor blocks from 803 pre-and postmenopausal cases by using real-time methylation-specific polymerase chain reaction. Unconditional logistic regression was used to derive the adjusted OR and 95% CI for case-case comparisons of tumors with and without promoter methylation of the genes. Results: The frequency of promoter methylation was 20% for E-cadherin, 25.9% for p16, and 27.5% for RAR-b 2 . There was no difference in the prevalence of the DNA methylation of individual genes by BMI, waist-to-hip ratio (WHR), or lifetime weight change between the age of 20 y and the present. However, in a case-case comparison of postmenopausal breast cancer, a greater WHR was associated with an increased likelihood of 1 of the 3 genes being methylated (OR: 1.85; 95% CI: 1.10, 3.11; P-trend , 0.02). Conclusions: We showed that WHR was associated with DNA promoter methylation of 1 of 3 genes in postmenopausal breast tumors. It may be that the association of body fat composition and postmenopausal breast cancer is related to altered DNA methylation. However, future studies in other populations and with an examination of the methylation of more genes are needed.Am J Clin Nutr 2011;94:831-8.

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DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study

Cited by 42 publications

References 30 publications

Loss of Expression and Aberrant Methylation of the CDH1 (E-cadherin) Gene in Breast Cancer Patients from Kashmir

Loss of Expression and Aberrant Methylation of the CDH1 (E-cadherin) Gene in Breast Cancer Patients from Kashmir

Promoter methylation and expression changes of CDH1 and P16 genes in invasive breast cancer and adjacent normal breast tissue

Body mass and DNA promoter methylation in breast tumors in the Western New York Exposures and Breast Cancer Study

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