Glycosylation of plasma IgG in colorectal cancer prognosis.

Evropi Theodoratou,Pauline M Rudd,Ewan Brown,Maja Pučić-Baković,Susan M Farrington,Harry Campbell,Anna Agakova,Gordan Lauc,Kujtim Thaçi,Peter Orchard,Farhat V N Din,Malcolm G Dunlop,Frano Vučković,Felix Agakov,Maria N Timofeeva,Jerko Štambuk

doi:10.1038/srep28098

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.

Highlights

Biomarkers for cancer and other diseases[5,6,7,8,9,10]
Immunoglobulins (Igs) are glycoprotein molecules made by plasma cells in response to challenge from antigens such as those associated with microbiological agents or cancer cells and there have been previous reports that IgG antibodies can act as independent cancer prognostic factors[15,16]
We explore the role of IgG glycosylation status as a novel prognostic biomarker of Colorectal cancer (CRC), and for classifying those patient groups with more aggressive tumours

Summary

Introduction

Biomarkers for cancer and other diseases[5,6,7,8,9,10]. technical challenges in analysing complex glycan structures have, far, hindered large scale investigation in human studies[4,11,12]. We explore the role of IgG glycosylation status as a novel prognostic biomarker of CRC, and for classifying those patient groups with more aggressive tumours. This is the first large-scale investigation of the role of IgG N-glycans in cancer prognosis and is made possible by recent technological developments[19]. We performed the first Genome Wide Association Study (GWAS) of the human IgG N-glycome and identified 9 single nucleotide polymorphisms (SNP) showing genome-wide association (p < 5 × 10−8)[20] This included the IKZF1 locus, which has been reported to be associated with the risk of various cancers[21] and appears to be a key regulator of IgG core-fucosylation. We explored the prognostic biomarker potential of IgG glycans after stage stratification to account for the different stage prognosis of CRC patients

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Conclusion