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Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen

(2012) EPIGENETICS. 7(7). p.701-709
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Bioinformatics: from nucleotids to networks (N2N)
Abstract
Breast cancer (BC) is a disease with diverse tumor heterogeneity, which challenges conventional approaches to develop biomarkers for early detection and prognosis. To identify effective biomarkers, we performed a genome-wide screen for functional methylation changes in BC, i.e., genes silenced by promoter hypermethylation, using a functionally proven gene expression approach. A subset of candidate hypermethylated genes were validated in primary BCs and tested as markers for detection and prognosis prediction of BC. We identified 33 cancer specific methylated genes and, among these, two categories of genes: (1) highly frequent methylated genes that detect early stages of BC. Within that category, we have identified the combination of NDRG2 and HOXD1 as the most sensitive (94%) and specific (90%) gene combination for detection of BC; (2) genes that show stage dependent methylation frequency pattern, which are candidates to help delineate BC prognostic signatures. For this category, we found that methylation of CDO1, CKM, CRIP1, KL and TAC1 correlated with clinical prognostic variables and was a significant prognosticator for poor overall survival in BC patients. CKM [Hazard ratio (HR) = 2.68] and TAC1 (HR = 7.73) were the strongest single markers and the combination of both (TAC1 and CKM) was associated with poor overall survival independent of age and stage in our training (HR = 1.92) and validation cohort (HR = 2.87). Our study demonstrates an efficient method to utilize functional methylation changes in BC for the development of effective biomarkers for detection and prognosis prediction of BC.
Keywords
functional hypermethylome screen, biomarker, detection, prognosis, COLORECTAL-CANCER, CPG ISLANDS, GENE, DNA, METHYLATION, SUSCEPTIBILITY, MUTATIONS, PROMOTER, breast cancer, INACTIVATION, RECURRENCE

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Citation

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Chicago
Jeschke, Jana, Leander Van Neste, Sabine C Glöckner, Mashaal Dhir, Marilia Freitas Calmon, Valerie Deregowski, Wim Van Criekinge, et al. 2012. “Biomarkers for Detection and Prognosis of Breast Cancer Identified by a Functional Hypermethylome Screen.” Epigenetics 7 (7): 701–709.
APA
Jeschke, J., Van Neste, L., Glöckner, S. C., Dhir, M., Calmon, M. F., Deregowski, V., Van Criekinge, W., et al. (2012). Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen. EPIGENETICS, 7(7), 701–709.
Vancouver
1.
Jeschke J, Van Neste L, Glöckner SC, Dhir M, Calmon MF, Deregowski V, et al. Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen. EPIGENETICS. 2012;7(7):701–9.
MLA
Jeschke, Jana, Leander Van Neste, Sabine C Glöckner, et al. “Biomarkers for Detection and Prognosis of Breast Cancer Identified by a Functional Hypermethylome Screen.” EPIGENETICS 7.7 (2012): 701–709. Print.
@article{3168766,
  abstract     = {Breast cancer (BC) is a disease with diverse tumor heterogeneity, which challenges conventional approaches to develop biomarkers for early detection and prognosis. To identify effective biomarkers, we performed a genome-wide screen for functional methylation changes in BC, i.e., genes silenced by promoter hypermethylation, using a functionally proven gene expression approach. A subset of candidate hypermethylated genes were validated in primary BCs and tested as markers for detection and prognosis prediction of BC. We identified 33 cancer specific methylated genes and, among these, two categories of genes: (1) highly frequent methylated genes that detect early stages of BC. Within that category, we have identified the combination of NDRG2 and HOXD1 as the most sensitive (94\%) and specific (90\%) gene combination for detection of BC; (2) genes that show stage dependent methylation frequency pattern, which are candidates to help delineate BC prognostic signatures. For this category, we found that methylation of CDO1, CKM, CRIP1, KL and TAC1 correlated with clinical prognostic variables and was a significant prognosticator for poor overall survival in BC patients. CKM [Hazard ratio (HR) = 2.68] and TAC1 (HR = 7.73) were the strongest single markers and the combination of both (TAC1 and CKM) was associated with poor overall survival independent of age and stage in our training (HR = 1.92) and validation cohort (HR = 2.87). Our study demonstrates an efficient method to utilize functional methylation changes in BC for the development of effective biomarkers for detection and prognosis prediction of BC.},
  author       = {Jeschke, Jana and Van Neste, Leander and Gl{\"o}ckner, Sabine C and Dhir, Mashaal and Calmon, Marilia Freitas and Deregowski, Valerie and Van Criekinge, Wim and Vlassenbroeck, Ilse and Koch, Alexander and Chan, Timothy A and Cope, Leslie and Hooker, Craig M and Schuebel, Kornel E and Gabrielson, Edward and Winterpacht, Andreas and Baylin, Stephen B and Herman, James G and Ahuja, Nita},
  issn         = {1559-2294},
  journal      = {EPIGENETICS},
  keyword      = {functional hypermethylome screen,biomarker,detection,prognosis,COLORECTAL-CANCER,CPG ISLANDS,GENE,DNA,METHYLATION,SUSCEPTIBILITY,MUTATIONS,PROMOTER,breast cancer,INACTIVATION,RECURRENCE},
  language     = {eng},
  number       = {7},
  pages        = {701--709},
  title        = {Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen},
  url          = {http://dx.doi.org/10.4161/epi.20445},
  volume       = {7},
  year         = {2012},
}

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