Carcinogenesis Advance Access published online on January 23, 2009
Carcinogenesis, doi:10.1093/carcin/bgp021
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Association between frequent CpG island methylation and HER2 amplification in human breast cancers
1 Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan
2 Department of Surgery, National Cancer Center Hospital, Tokyo, Japan
3 Institute for Clinical Research, National Hospital Organization Kure Medical Center / Chugoku Cancer Center, Hiroshima, Japan
4 Pathology Laboratory, National Cancer Center Hospital, Tokyo, Japan
5 Department of Surgical Metabolic Care and Endocrine Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Correspondence to T. U. at tushijim{at}ncc.go.jp, fax +81 3 5565 1753, phone +81 3 3547 5240, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
The presence of frequent methylation of CpG islands, designated as the CpG island methylator phenotype in some cancers, is associated with distinct clinicopathological characteristics, including gene amplification, in individual tumor types. Amplification of HER2 in human breast cancers is an important prognostic and therapeutic target, but an association between HER2 amplification and frequent CpG island methylation is unknown. To clarify the association, we here quantified methylation levels of promoter CpG islands of 11 genes, which are unlikely to confer growth advantage to cells, in 63 human breast cancers. The number of methylated genes in a cancer did not obey a bimodal distribution, and the 63 cancers were classified into those with frequent methylation (n = 16), moderate methylation (n = 26), and no methylation (n = 21). The incidence of HER2 amplification was significantly higher in the cancers with frequent methylation (11 of 16) than in those with no methylation (2 of 21, P=0.001). Also, the number of methylated genes correlated with the degree of HER2 amplification (r = 0.411, P=0.002). Correlation analysis with clinicopathological characteristics and methylation of CDKN2A, BRCA1, and CDH1 revealed that frequent methylation had significant correlation with higher nuclear grades (P=0.001). These showed that frequent methylation had a strong association with HER2 amplification in breast cancers, and suggested that frequent methylation can be a determinant of various characteristics in a fraction of human breast cancers.
Key Words: DNA methylation • epigenetics • HER2 amplification • breast cancers
Received August 20, 2008; revised December 16, 2008; accepted January 11, 2009.