Abstract
Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis. We examined whether promoter hypermethylation contributes to the pathogenesis of benign breast lesions along a progression continuum to invasive breast cancer. The exploratory study cohort comprised 17 breast cancer patients with multiple benign and/or in situ lesions concurrently present with invasive carcinoma within a tumor biopsy. DNA from tumor tissue, normal breast epithelium when present, benign lesions (fibroadenoma, hyperplasia, papilloma, sclerosing adenosis, apocrine metaplasia, atypical lobular hyperplasia or atypical ductal hyperplasia), and in situ lesions of lobular carcinoma and ductal carcinoma were interrogated for promoter methylation status in 22 tumor suppressor genes using the multiplex ligation-dependent probe amplification assay (MS-MLPA). Methylation specific PCR was performed to confirm hypermethylation detected by MS-MLPA. Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases. Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer. Hypermethylated promoter regions in normal breast epithelium, benign, and premalignant lesions within the same tumor biopsy implicate RASSF1, APC, GSTP1, TIMP3, CDKN2B, CDKN2A, ESR1, CDH13, RARB, CASP8, and TP73 as early events. DNA hypermethylation underlies the pathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer.
Highlights
Progression from a pre-malignant lesion to malignancy is associated with cytogenetic and molecular genetic aberrations [1,2,3]
We examined whether promoter hypermethylation contributes to the pathogenesis of benign and premalignant breast lesions along a progression continuum to invasive breast cancer
DNA was obtained from 71 lesions, and included 15 normal, 16 benign, 11 carcinoma-insitu (CIS) and 29 tumor lesions, which were interrogated for methylation status using the Methylation-Specific Multiplex Ligation Dependent Probe Amplification (MS-MLPA) assay (Table 1)
Summary
Progression from a pre-malignant lesion to malignancy is associated with cytogenetic and molecular genetic aberrations [1,2,3]. Epigenetics is the regulation of changes in gene expression by mechanisms that do not involve changes in DNA sequence. Establishment and maintenance of epigenetic control (gene silencing) has several aspects, which include promoter region hypermethylation, methyl-binding proteins, DNA methyltransferases, histone deacetylases and chromatin state. Epigenetic alterations, in particular promoter hypermethylation, are proving to be consistent and early events in neoplastic progression [6,7,8,9]. Such alterations are thought to contribute to the neoplastic process by transcriptional silencing of tumor suppressor gene expression and by increasing the rate of genetic mutation [10,11]
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