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

Yoon Hee Cho, Jing Shen, Marilie D. Gammon, Yu Jing Zhang, Qiao Wang, Karina Gonzalez, Xinran Xu, Patrick T. Bradshaw, Susan L. Teitelbaum, Gail Garbowski, Hanina Hibshoosh, Alfred I. Neugut, Jia Chen, Regina M. Santella

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68 Scopus citations


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.

Original languageEnglish
Pages (from-to)197-205
Number of pages9
JournalBreast Cancer Research and Treatment
Issue number1
StatePublished - Jan 2012


  • Breast cancer
  • Mortality
  • Promoter methylation
  • Tumor suppressor gene


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