title: Integrated analysis of DNA methylation, immunohistochemistry and mRNA expression, data identifies a methylation expression index (MEI) robustly associated with survival of ER-positive breast cancer patients.
abstract: Identification of prognostic gene expression signatures may enable improved decisions about management of breast cancer. To identify a prognostic signature for breast cancer, we performed DNA methylation profiling and identified methylation markers that were associated with expression of ER, PR, HER2, CK5/6, and EGFR proteins. Methylation markers that were correlated with corresponding mRNA expression levels were identified using 208 invasive tumors from a population-based case-control study conducted in Poland. Using this approach, we defined the methylation expression index (MEI) signature that was based on a weighted sum of mRNA levels of 57 genes. Classification of cases as low or high MEI scores was related to survival using Cox regression models. In the Polish study, women with ER-positive low MEI cancers had reduced survival at a median of 5.20 years of follow-up, HR = 2.85 95 % CI = 1.25-6.47. Low MEI was also related to decreased survival in four independent datasets totaling over 2500 ER-positive breast cancers. These results suggest that integrated analysis of tumor expression markers, DNA methylation, and mRNA data may be an important approach for identifying breast cancer prognostic signatures. Prospective assessment of MEI along with other prognostic signatures should be evaluated in future studies.
authors.affiliation: National Cancer Institute, NIH, HHS, Bethesda, MD.
authors.forename: Jonine D
authors.initials: JD
authors.lastname: Figueroa
authors.affiliation: National Cancer Institute, NIH, HHS, Bethesda, MD.
authors.forename: Howard
authors.initials: H
authors.lastname: Yang
authors.affiliation: Institute for Cancer Research, London, UK.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.affiliation: National Cancer Institute, NIH, HHS, Bethesda, MD.
authors.forename: Sean
authors.initials: S
authors.lastname: Davis
authors.affiliation: National Cancer Institute, NIH, HHS, Bethesda, MD.
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
authors.affiliation: Department of Cancer Epidemiology and Prevention, Cancer Center and M. Sklodowska-Curie Institute of Oncology, Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.affiliation: National Cancer Institute, NIH, HHS, Bethesda, MD.
authors.forename: Hisani N
authors.initials: HN
authors.lastname: Horne
authors.affiliation: National Cancer Institute, NIH, HHS, Bethesda, MD.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sherman
authors.affiliation: National Cancer Institute, NIH, HHS, Bethesda, MD.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D016022:Case-Control Studies; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D011960:Receptors, Estrogen