title: A seven-gene CpG-island methylation panel predicts breast cancer progression.
abstract: BACKGROUND
  DNA methylation regulates gene expression, through the inhibition/activation of gene transcription of methylated/unmethylated genes. Hence, DNA methylation profiling can capture pivotal features of gene expression in cancer tissues from patients at the time of diagnosis. In this work, we analyzed a breast cancer case series, to identify DNA methylation determinants of metastatic versus non-metastatic tumors.
  
  
  METHODS
  CpG-island methylation was evaluated on a 56-gene cancer-specific biomarker microarray in metastatic versus non-metastatic breast cancers in a multi-institutional case series of 123 breast cancer patients. Global statistical modeling and unsupervised hierarchical clustering were applied to identify a multi-gene binary classifier with high sensitivity and specificity. Network analysis was utilized to quantify the connectivity of the identified genes.
  
  
  RESULTS
  Seven genes (BRCA1, DAPK1, MSH2, CDKN2A, PGR, PRKCDBP, RANKL) were found informative for prognosis of metastatic diffusion and were used to calculate classifier accuracy versus the entire data-set. Individual-gene performances showed sensitivities of 63-79 %, 53-84 % specificities, positive predictive values of 59-83 % and negative predictive values of 63-80 %. When modelled together, these seven genes reached a sensitivity of 93 %, 100 % specificity, a positive predictive value of 100 % and a negative predictive value of 93 %, with high statistical power. Unsupervised hierarchical clustering independently confirmed these findings, in close agreement with the accuracy measurements. Network analyses indicated tight interrelationship between the identified genes, suggesting this to be a functionally-coordinated module, linked to breast cancer progression.
  
  
  CONCLUSIONS
  Our findings identify CpG-island methylation profiles with deep impact on clinical outcome, paving the way for use as novel prognostic assays in clinical settings.
authors.affiliation: Rush University Medical Center, 653 W Congress Pkwy, Chicago, IL, 60612, USA. yan_li2@rush.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: US Biomarkers, Inc, 29 Buckingham Ln., Buffalo Grove, IL, 60089, USA. anatoliy@usbiomarkers.com.
authors.forename: Anatoliy A
authors.initials: AA
authors.lastname: Melnikov
authors.affiliation: US Biomarkers, Inc, 29 Buckingham Ln., Buffalo Grove, IL, 60089, USA. victor@usbiomarkers.com.|Currently at Center for Translational Research, Catholic Health Initiatives, Englewood, USA. victor@usbiomarkers.com.
authors.forename: Victor
authors.initials: V
authors.lastname: Levenson
authors.affiliation: Unit of Cancer Pathology, CeSI, 'G. d'Annunzio' University Foundation, Via L. Polacchi 11, 66100, Chieti, Italy. emanuela.guerra5@gmail.com.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Guerra
authors.affiliation: Unit of Cancer Pathology, CeSI, 'G. d'Annunzio' University Foundation, Via L. Polacchi 11, 66100, Chieti, Italy. simeone.pasquale@gmail.com.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Simeone
authors.affiliation: Unit of Cancer Pathology, CeSI, 'G. d'Annunzio' University Foundation, Via L. Polacchi 11, 66100, Chieti, Italy. s.alberti@unich.it.|Department of Neuroscience, Imaging and Clinical Sciences, Unit of Physiology and Physiopathology, 'G. d'Annunzio' University, Via dei Vestini, 66100, Chieti, Italy. s.alberti@unich.it.
authors.forename: Saverio
authors.initials: S
authors.lastname: Alberti
authors.affiliation: Rush University Medical Center, 653 W Congress Pkwy, Chicago, IL, 60612, USA. Youping_Deng@rush.edu.
authors.forename: Youping
authors.initials: Y
authors.lastname: Deng
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009362:Neoplasm Metastasis; D011379:Prognosis; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor