Promoter hypermethylation in sentinel lymph nodes as a marker for breast cancer recurrence

Abstract

Purpose-Promoter methylation of tumor suppressor genes in histologically negative sentinel lymph nodes (HNSN) of early stage breast cancer patients has not been extensively studied. This study evaluates the methylation frequency and pattern in HNSN to determine if detection of hypermethylation of one or more genes is associated with an increased recurrence risk in node negative breast cancer.Experimental design-In 1998, a prospective study of patients with early stage breast cancer and HNSN was initiated in order to correlate sentinel node analysis with clinical outcome. Nodal tissue was selected from 120 HNSN patients for methylation analysis in at least one and up to six sentinel nodes using a panel of nine genes. Corresponding primary breast tumors from 79 patients were also evaluated for hypermethylation. Methylation analysis was performed using nested Methylation Sensitive PCR (n-MSP). Logistical regression was used to evaluate the relationship between clinical recurrence and methylation status.Results-Over a median follow-up of 79 months, 13 of the 120 patients had clinical recurrence. Hypermethylation of genes was frequently observed in HNSN, but there was no correlation of methylation pattern and clinical recurrence. However, increased frequency of gene methylation of the primary tumor correlated with clinical recurrence.Conclusions-Although hypermethylation of multiple genes occurs frequently in HNSN of breast cancer patients, it is not associated with breast cancer recurrence in the first 7 years of clinical follow-up.

Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation

“…Normal peripheral blood monocytes from normal donors ( n = 5) were unmethylated for these 12 genes (data not shown) as previously reported [15,23,26]. There were no significant differences in the frequency of methylation between the entire AML group ( n = 169) and the patients with normal karyotype leukemia ( n = 106).…”

“…In addition, we collected clinical outcome information on all-cause mortality and disease-free status. A series of 54 stage I ductal breast adenocarcinoma samples procured for a previous study [26] were used as a basis for comparison between the Wnt inhibitor methylation profile of epithelial versus hematological malignancies. In accordance with HIPAA regulations (Health Insurance Portability and Accountability Act), all clinical samples were obtained as part of a protocol approved by the Institutional Review Board (IRB) at the Johns Hopkins Hospital.…”

Tumor suppressor genes are frequently methylated in lymph node metastases of breast cancers

“…Carraway et al reported that in the early stage cancer (lymph node negative) methylation changes can predict the recurrence [19]. In this study, we studied the methylation status in metastasis lymph nodes and found that methylation changes which already accumulated in primary cancer were continued in metastatic tumors.…”

Cancer DNA Methylation: Molecular Mechanisms and Clinical Implications

“…A 4-marker panel including p16 , H-cadherin , APC , and RASSF1A was associated with a higher risk of recurrence in resected early stage lung cancer, particularly when simultaneous methylation of two markers ( p16 and H-cadherin ) was present in both primary tumor and histologically negative mediastinal lymph nodes (OR for recurrence 15.5) (117). Similar relationships exist between the number of methylated genes and risk of relapse in breast and prostate cancer (118-120). …”