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

  • Epidemiology
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Abstract

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.

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Acknowledgment

This work was supported by a grant from the National Institutes of Health (CA109753 to JC) and in part by grants from Department of Defense (BC031746), National Cancer Institute and the National Institutes of Environmental Health and Sciences (UO1CA/ES66572, UO1CA66572, P30CA013696, P30ES009089, and P30ES10126); Xu, X. is a recipient of the Predoctoral Traineeship Award (W81XWH-06-1-0298) of Department of Defense Breast Cancer Research Program.

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Authors and Affiliations

  1. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 630 West 168th St, New York, NY, 10032, USA

    Yoon Hee Cho, Jing Shen, Yu-Jing Zhang, Qiao Wang, Karina Gonzalez, Gail Garbowski & Regina M. Santella

  2. Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA

    Marilie D. Gammon & Patrick T. Bradshaw

  3. Departments of Preventive Medicine, Mount Sinai School of Medicine, New York, NY, USA

    Xinran Xu, Susan L. Teitelbaum & Jia Chen

  4. Department of Pathology, Columbia University, 630 West 168th St, New York, NY, 10032, USA

    Hanina Hibshoosh

  5. Department of Epidemiology, Columbia University, 630 West 168th St, New York, NY, 10032, USA

    Alfred I. Neugut

  6. Department of Medicine, Columbia University, 630 West 168th St, New York, NY, 10032, USA

    Alfred I. Neugut

  7. Departments of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA

    Jia Chen

  8. Departments of Oncological Science, Mount Sinai School of Medicine, New York, NY, USA

    Jia Chen

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  1. Yoon Hee Cho
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  2. Jing Shen
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  7. Xinran Xu
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  8. Patrick T. Bradshaw
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  12. Alfred I. Neugut
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Correspondence to Regina M. Santella.

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Yoon Hee Cho and Jing Shen contributed equally to this manuscript.

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Cho, Y.H., Shen, J., Gammon, M.D. et al. Prognostic significance of gene-specific promoter hypermethylation in breast cancer patients. Breast Cancer Res Treat 131, 197–205 (2012). https://doi.org/10.1007/s10549-011-1712-y

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  • DOI: https://doi.org/10.1007/s10549-011-1712-y

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