Carcinogenesis Advance Access originally published online on January 23, 2009
Carcinogenesis 2009 30(3):466-471; doi:10.1093/carcin/bgp021
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Association between frequent CpG island methylation and HER2 amplification in human breast cancers
1 Carcinogenesis Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2 Department of Surgical Metabolic Care and Endocrine Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
3 Department of Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
4 Institute for Clinical Research, National Hospital Organization Kure Medical Center/Chugoku Cancer Center, Hiroshima 737-0023, Japan
5 Pathology Laboratory, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
* To whom correspondence should be addressed. Tel: +81 3 3547 5240; Fax: +81 3 5565 1753; Email: tushijim{at}ncc.go.jp
The presence of frequent methylation of CpG islands (CGIs), 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 CGI methylation is unknown. To clarify the association, we here quantified methylation levels of promoter CGIs 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.
Abbreviations: CGI, CpG island; CIMP, CpG island methylator phenotype; ESR, estrogen receptor; PCR, polymerase chain reaction; PGR, progesterone receptor
Received August 20, 2008; revised December 16, 2008; accepted January 11, 2009.