title: Methylation of CpG islands of p16(INK4a) and cyclinD1 overexpression associated with progression of intraductal proliferative lesions of the breast.
abstract: P16(INK4a) is a tumor suppressor gene frequently inactivated by aberrant promoter hypermethylation. In this study, p16(INK4a) methylation was evaluated in intraductal proliferative lesions of the breast, using real-time quantitative polymerase chain reaction (MethyLight) and methylation-sensitive restriction endonuclease polymerase chain reaction. Immunohistochemistry was performed to compare and validate the methylation analysis. P16(INK4a) methylation associated with oncogene cyclinD1 expression, detected through the use of in situ hybridization and immunohistochemistry, was likewise characterized. P16(INK4a) methylation displayed varying significance among different types of intraductal proliferative lesions. Both the positive rate and the median quantitative methylation value increased with the evolution of intraductal proliferative lesions through the use of quantitative and qualitative assays. P16(INK4a) methylation was positively correlated to cyclinD1 overexpression. This study demonstrated that p16(INK4a) methylation served as the silencing mechanism of p16(INK4a) protein expression and played a crucial role in the intraductal proliferative lesions' progression. In the differential diagnosis of intraductal proliferative lesions, quantitative DNA methylation analysis of p16(INK4a) by MethyLight may be used as a surrogate, especially to distinguish atypical ductal hyperplasia from usual ductal hyperplasia and low-grade ductal carcinoma in situ. Furthermore, this study discovered that flat epithelial atypia do not share similar molecular profiles of p16(INK4a) epigenetic modification with atypical ductal hyperplasia and low-grade ductal carcinoma in situ.
authors.affiliation: Breast Cancer Research Key Laboratory of National (Education Ministry), Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
authors.forename: Tieju
authors.initials: T
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Niu
authors.forename: Yumei
authors.initials: Y
authors.lastname: Feng
authors.forename: Ruifang
authors.initials: R
authors.lastname: Niu
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.forename: Ajuan
authors.initials: A
authors.lastname: Lv
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
mesh_terms: D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands / Q000502:physiology*; D019938:Cyclin D1 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D006801:Humans
chemical_list: C530104:CCND1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019938:Cyclin D1