Diagnostic and Prognostic Value of B4GALT1 Hypermethylation and Its Clinical Significance as a Novel Circulating Cell-Free DNA Biomarker in Colorectal Cancer

19 Oct 2019Cancers

DOI : 10.3390/cancers11101598

Authors

Francesco Picardo, Antonella Romanelli, Laura Muinelo-Romay, Tommaso Mazza, Caterina Fusilli, Paola Parrella, Jorge Barbazán, Rafael Lopez-López, Raffaela Barbano, Mariangela De Robertis, Chiara Taffon, Veronica Bordoni, Chiara Agrati, Manuela Costantini, Francesca Ricci, Paolo Graziano, Evaristo Maiello, Lucia Anna Muscarella, Vito Michele Fazio, Maria Luana Poeta

Abstract

Epigenetic modifications of glyco-genes have been documented in different types of cancer and are tightly linked to proliferation, invasiveness, metastasis, and drug resistance. This study aims to investigate the diagnostic, prognostic, and therapy-response predictive value of the glyco-gene B4GALT1 in colorectal cancer (CRC) patients. A Kaplan–Meier analysis was conducted in 1418 CRC patients (GEO and TCGA datasets) to assess the prognostic and therapy-response predictive values of the aberrant expression and methylation status of B4GALT1. Quantitative methylation-specific PCR (QMSP) and droplet digital quantitative methylation-specific PCR (dd-QMSP) were respectively used to detect hypermethylated B4GALT1 in metastasis and plasma in four cohorts of metastatic CRC cases (mCRC). Both the downregulated expression and promoter hypermethylation of B4GALT1 have a negative prognostic impact on CRC. Interestingly a low expression level of B4GALT1 was significantly associated with poor cetuximab response (progression-free survival (PFS) p = 0.01) particularly in wild-type (WT)-KRAS patients (p = 0.03). B4GALT1 promoter was aberrantly methylated in liver and lung metastases. The detection of hypermethylated B4GALT1 in plasma of mCRC patients showed a highly discriminative receiver operating characteristic (ROC) curve profile (area under curve (AUC) value 0.750; 95% CI: 0.592–0.908, p = 0.008), clearly distinguishing mCRC patients from healthy controls. Based on an optimal cut-off value defined by the ROC analysis, B4GALT1 yield a 100% specificity and a 50% sensitivity. These data support the potential value of B4GALT1 as an additional novel biomarker for the prediction of cetuximab response, and as a specific and sensitive diagnostic circulating biomarker that can be detected in CRC.