Glycosylation of plasma IgG in colorectal cancer prognosis

Abstract

In this study we demonstrate the potential value of Immunoglobulin G (IgG) glycosylation as a novel prognostic biomarker of colorectal cancer (CRC). We analysed plasma IgG glycans in 1229 CRC patients and correlated with survival outcomes. We assessed the predictive value of clinical algorithms and compared this to algorithms that also included glycan predictors. Decreased galactosylation, decreased sialylation (of fucosylated IgG glycan structures) and increased bisecting GlcNAc in IgG glycan structures were strongly associated with all-cause (q < 0.01) and CRC mortality (q = 0.04 for galactosylation and sialylation). Clinical algorithms showed good prediction of all-cause and CRC mortality (Harrell's C: 0.73, 0.77; AUC: 0.75, 0.79, IDI: 0.02, 0.04 respectively). The inclusion of IgG glycan data did not lead to any statistically significant improvements overall, but it improved the prediction over clinical models for stage 4 patients with the shortest follow-up time until death, with the median gain in the test AUC of 0.08. These glycan differences are consistent with significantly increased IgG pro-inflammatory activity being associated with poorer CRC prognosis, especially in late stage CRC. In the absence of validated biomarkers to improve upon prognostic information from existing clinicopathological factors, the potential of these novel IgG glycan biomarkers merits further investigation.

Figure 1. UPLC analysis of immunoglobulin G (IgG) glycosylation.

Each IgG contains one conserved N-glycosylation site on Asn197 of its heavy chain. Different glycans can be attached to this site and the process seems to be highly regulated. UPLC analysis can reveal composition of the glycome attached to a population of IgG molecules by separating total IgG N-glycome into 24 chromatographic glycan peaks (GP1–GP24), mostly corresponding to individual glycan structures.

Figure 2. Manhattan-type plot of the association FDR corrected p values (q-values) of all 39 glycan variables for all–cause (red dots) and CRC-specific (blue dots) mortality adjusted for AJCC CRC stage, age, sex, time between sample and surgery, operation type, CRP and BMI (Model II).

Analysed glycans are plotted on the X-axis. Y-axis plots the – logarithm of the q values. The names of glycans, which associations achieved statistical significance after correction for multiple testing (q < 0.05), are named in the plot. Details of the association analysis results are presented in Table 2 and cartoon structures of the glycans are presented in Fig. 1.