Evaluation of the adenocarcinoma-associated gene AGR2 and the intestinal stem cell marker LGR5 as biomarkers in colorectal cancer

Int J Mol Sci. 2012;13(4):4367-87. doi: 10.3390/ijms13044367. Epub 2012 Apr 5.

Abstract

We aim to estimate the diagnostic performances of anterior gradient homolog-2 (AGR2) and Leucine-rich repeat-containing-G-protein-coupled receptor 5 (LGR5) in peripheral blood (PB) as mRNA biomarkers in colorectal cancer (CRC) and to explore their prognostic significance. Real-time PCR was used to analyze AGR2 and LGR5 in 54 stages I-IV CRC patients and 19 controls. Both mRNAs were significantly increased in PB from CRC patients compared to controls. The area under the receiver-operating characteristic curves were 0.722 (p = 0.006), 0.376 (p = 0.123) and 0.767 (p = 0.001) for AGR2, LGR5 and combined AGR2/LGR5, respectively. The AGR2/LGR5 assay resulted in 67.4% sensitivity and 94.7% specificity. AGR2 correlated with pT3-pT4 and high-grade tumors. LGR5 correlated with metastasis, R2 resections and high-grade. The progression-free survival (PFS) of patients with high AGR2 was reduced (p = 0.037; HR, 2.32), also in the stage I-III subgroup (p = 0.046). LGR5 indicated a poor prognosis regarding both PFS (p = 0.007; HR, 1.013) and overall survival (p = 0.045; HR, 1.01). High AGR2/LGR5 was associated with poor PFS (p = 0.014; HR, 2.8) by multivariate analysis. Our findings indicate that the assessment of AGR2 and LGR5 in PB might reflect the presence of circulating tumor cells (CTC) and stem cell like CTC in CRC. Increased AGR2 and LGR5 are associated with poor outcomes.

Keywords: anterior gradient homolog-2; circulating tumor cells; colorectal cancer; leucine-rich repeat-containing G-protein-coupled receptor 5; prognostic markers; real-time PCR; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality*
  • Colorectal Neoplasms / pathology
  • Disease-Free Survival
  • Female
  • Humans
  • Lymphatic Metastasis / genetics
  • Lymphatic Metastasis / pathology
  • Male
  • Middle Aged
  • Mucoproteins
  • Neoplasm Staging
  • Neoplastic Cells, Circulating / pathology
  • Neoplastic Stem Cells / pathology
  • Oncogene Proteins
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Messenger / genetics
  • Receptors, G-Protein-Coupled / blood*
  • Receptors, G-Protein-Coupled / genetics
  • Survival Analysis

Substances

  • AGR2 protein, human
  • Biomarkers, Tumor
  • LGR5 protein, human
  • Mucoproteins
  • Oncogene Proteins
  • Proteins
  • RNA, Messenger
  • Receptors, G-Protein-Coupled