title: Prognostic significance of gene-specific promoter hypermethylation in breast cancer patients.
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.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 630 West 168th St, New York, NY 10032, USA.
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Cho
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wang
authors.forename: Karina
authors.initials: K
authors.lastname: Gonzalez
authors.forename: Xinran
authors.initials: X
authors.lastname: Xu
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Bradshaw
authors.forename: Susan L
authors.initials: SL
authors.lastname: Teitelbaum
authors.forename: Gail
authors.initials: G
authors.lastname: Garbowski
authors.forename: Hanina
authors.initials: H
authors.lastname: Hibshoosh
authors.forename: Alfred I
authors.initials: AI
authors.lastname: Neugut
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.forename: Regina M
authors.initials: RM
authors.lastname: Santella
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011795:Surveys and Questionnaires; D051879:Twist-Related Protein 1 / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C082925:retinoic acid receptor beta; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi