Prognostic significance of gene-specific promoter hypermethylation in breast cancer patients

The association between promoter methylation status and survival was investigated in a large cohort of women with breast cancer, participants in the Long Island Breast Cancer Study Project. Archived tumor tissues (n = 839) were collected from women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997. Vital status was followed through the end of 2005 with a mean follow-up time of 8 years. Promoter methylation of eight breast cancer-related genes was assessed by MethyLight. The frequencies of methylation for HIN1, RASSF1A, DAPK1, GSTP1, CyclinD2, TWIST, CDH1 and RARβ were 62.9, 85.2, 14.1, 27.8, 19.6, 15.3, 5.8 and 27.6%, respectively. Since survival rates of in situ and invasive breast cancers are substantially different, survival analyses were conducted within 670 invasive cases with complete data on all genes. Age-adjusted Cox proportional hazards models revealed that GSTP1, TWIST and RARβ methylation was significantly associated with higher breast cancer-specific mortality. Methylation of GSTP1 and RARβ was significantly associated with higher all-cause mortality. To investigate the relationship between the number of methylated genes and breast cancer-specific mortality, we included previously published MethyLight data on p16 and APC methylation status. Breast cancer-specific mortality increased in a dose-dependent manner with increasing number of methylated genes (P _trend = 0.002), although confidence intervals were wide. Our results suggest that promoter methylation, particularly for a panel of genes, has the potential to be used as a biomarker for predicting prognosis in breast cancer.