Diagnostic and prognostic value of B4GALT1 hypermethylation and its clinical significance as a novel circulating cell-free DNA biomarker in colorectal cancer

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number1598
Pages (from-to)1-16
Number of pages16
JournalCancers
Volume11
Issue number10
DOIs
Publication statusPublished - Oct 2019

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Keywords

  • B4GALT1
  • Cetuximab
  • CfDNA
  • Colorectal cancer
  • Liquid biopsy
  • Predictive biomarker

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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