title: Aberrant promoter methylation of beta-1,4 galactosyltransferase 1 as potential cancer-specific biomarker of colorectal tumors.
abstract: Epigenetic alterations, such as CpG islands methylation and histone modifications, are recognized key characteristics of cancer. Glycogenes are a group of genes which epigenetic status was found to be changed in several tumors. In this study, we determined promoter methylation status of the glycogene beta-1,4-galactosyltransferase 1 (B4GALT1) in colorectal cancer patients. Methylation status of B4GALT1 was assessed in 130 colorectal adenocarcinomas, 13 adenomas, and in paired normal tissue using quantitative methylation specific PCR (QMSP). B4GALT1 mRNA expression was evaluated in methylated/unmethylated tumor and normal specimens. We also investigated microsatellite stability and microsatellite instability status and KRAS/BRAF mutations. Discriminatory power of QMSP was assessed by receiving operating curve (ROC) analysis on a training set of 24 colorectal cancers and paired mucosa. The area under the ROC curve (AUC) was 0.737 (95% confidence interval [CI]:0.591-0.881, P = 0.005) with an optimal cutoff value of 2.07 yielding a 54% sensitivity (95% CI: 35.1%-72.1%) and a specificity of 91.7% (95% CI: 74.1%-97.7%). These results were confirmed in an independent validation set where B4GALT1 methylation was detected in 52/106 patients. An inverse correlation was observed between methylation and B4GALT1 mRNA expression levels (r = -0.482, P = 0.037). Significant differences in methylation levels and frequencies was demonstrated in invasive lesions as compared with normal mucosa (P = 0.0001) and in carcinoma samples as compared with adenoma (P = 0.009). B4GALT1 methylation is a frequent and specific event in colorectal cancer and correlates with downregulation of mRNA expression. These results suggest that the glycogene B4GALT1 represent a valuable candidate biomarker of invasive phenotype of colorectal cancer.
authors.affiliation: Department of Bioscience, Biotechnology and Pharmacological Sciences, University of Bari, Italy. poetaluana@gmail.com
authors.forename: Maria Luana
authors.initials: ML
authors.lastname: Poeta
authors.forename: Emanuela
authors.initials: E
authors.lastname: Massi
authors.forename: Paola
authors.initials: P
authors.lastname: Parrella
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pellegrini
authors.forename: Mariangela
authors.initials: M
authors.lastname: De Robertis
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.forename: Carla
authors.initials: C
authors.lastname: Rabitti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perrone
authors.forename: Andrea Onetti
authors.initials: AO
authors.lastname: Muda
authors.forename: Francesca
authors.initials: F
authors.lastname: Molinari
authors.forename: Elena
authors.initials: E
authors.lastname: Zanellato
authors.forename: Stefano
authors.initials: S
authors.lastname: Crippa
authors.forename: Damiano
authors.initials: D
authors.lastname: Caputo
authors.forename: Marco
authors.initials: M
authors.lastname: Caricato
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.forename: Roberto
authors.initials: R
authors.lastname: Coppola
authors.forename: Vito Michele
authors.initials: VM
authors.lastname: Fazio
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D005700:Galactosyltransferases; C119701:beta-1,4-galactosyltransferase I; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins