Methylation-dependent transcriptional silencing of Dab2 is a common early event in human tumorigenesis and predicts metastasis

Abstract

9536 Background: Using pharmacological reversal of methylation, we identified Dab2 as a gene whose expression is silenced by methylation in squamous and breast carcinoma cell lines. Methods: We subsequently used methylation-specific PCR (MSP) to analyse methylation of Dab2 in large series of primary and metastatic carcinomas of the head and neck (HNSCC) and breast. Results: These studies identified methylation-dependent transcriptional silencing of Dab2 in 42% of advanced HNSCC and 39% of breast cancers. In breast cancer, the frequency of Dab2 methylation increased with increasing histological grade. Dab2 methylation was detectable in pre-malignant oral dysplastic lesions and in breast ductal carcinoma in situ, implying that silencing of the gene is an early event in tumorigenesis in these tissues. The hypothesis that loss of Dab2 expression is an early event in epithelial tumorigenesis was further verified by analysis of anogenital squamous cell cancers, wherein methylation of the gene was detecteable in histologically confimed pre-invasive, intra-epithelial neoplastic lesions. Furthermore, methylation of Dab2 was closely associated with metastasis in breast and HNSCC and with less favourable clinical outcome in both tumor types. Conclusions: These results identify Dab2 as gene frequently subject to transcriptional silencing in human solid tumors and imply that analysis of Dab2 methylation/expressive may have utility in identification of individual cancers at high risk of clinically aggressive disease. No significant financial relationships to disclose.