Immunoglobulin G glycosylation in patients with colorectal cancer

doctoral thesis

• Author: Kujtim Thaçi
• Mentor: Gordan Lauc (mentor)
• Committee member: nije dostupno (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2017-11-27, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences
• Universal decimal classification (UDC): 61 - Medical sciences

Abstract

UVOD: Rak debelog crijeva je zloćudna novotvorina debelog crijeva i rektuma, te je još uvijek povezan s lošom prognozom, niskom stopom preživljavanja i vrlo često relativno kasnom dijagnozom.
MATERIJALI I METODE: Analizirali smo glikozilaciju imunoglobulina G (IgG) u populaciji od 1229 ljudi oboljenih od raka debelog crijeva te 538 odgovarajućih kontrolnih uzoraka. Utjecaj operacije na glikozilaciju procjenjen je kod 28 bolesnika uzorkovanih prije i tri puta nakon operacije. Nadalje, glikozilacija IgG-a analizirana je i u 39 uzoraka krvne plazme izuzete prije prve dijagnoze.
REZULTATI: Klinički algoritmi pokazali su dobro predviđanje ukupne smrtnosti kao i smrtnosti uzrokovane rakom debelog crijeva. Uključivanje podataka o IgG glikanima u regresijske modele nije dovelo do statistički značajnog poboljšanja u ukupnoj prognozi preživljavanja (Harrellov C indeks: 0.73, 0.77; AUC: 0.75, 0.79; IDI: 0.02, 0.04). Međutim, u odnosu na modele temeljene isključivo na kliničkim podacima uključivanjem podataka o IgG glikanima značajno je poboljšano predviđanje “rapidnih progresora” kod bolesnika u AJCC četvrtoj fazi (AUC 0.53 vs 0.75, IDI 0.21). Analizom kliničkih podataka 760 pacijenata i 538 odgovarajućih kontrola utvrđena je povezanost raka debelog crijeva s padom stupnja galaktozilacije i sijalinizacije IgG glikana, s porastom fukozilacije neutralnih IgG glikana te padom fukozilacije sijaliniziranih IgG glikana.
ZAKLJUČAK: Karakteristike glikozilacije IgG-a kod pacijenata oboljelih od raka debelog crijeva u skladu su sa značajno povećanom proupalnom aktivnošću IgG-a povezanom s lošijom prognozom, pogotovo u kasnijem stadiju. S obzirom na funkcionalnu važnost glikozilacije IgG-a u imunološkom nadzoru i učinkovitosti terapije monoklonskim antitijelima, individualne varijacije u glikozilaciji IgG-a mogle bi imati važnu ulogu u predviđanju tijeka bolesti ili izboru terapije.

Abstract (croatian)

INTRODUCTION: Colorectal cancer (CRC) is a malignant neoplasm of the colon and the rectum. CRC is still associated with poor prognosis, low survival rate and usually relatively late diagnosis.
MATERIALS AND METHODS: We analysed IgG glycome composition in 1229 patients with CRC and 538 matching controls. Effects of surgery were evaluated in 28 patients sampled before and three times after surgery. Furthermore, IgG glycome composition was analysed in 39 plasma samples collected before initial diagnosis of CRC.
RESULTS: Clinical algorithms showed good prediction of all cause and CRC mortality. The inclusion of IgG glycan data in regression models did not lead to any statistically significant improvements in overall prediction of survival (Harrell’s C: 0.73, 0.77; AUC: 0.75, 0.79, IDI: 0.02, 0.04 respectively). However, the inclusion of IgG glycan data substantially improved the prediction of rapid progressors over clinical models in AJCC stage 4 patients (AUC 0.53 vs. 0.75, IDI 0.21). When analysing clinical characteristics among 760 patients and 538 matching controls it was found that CRC associates with decrease in IgG galactosylation, IgG sialylation and increase in core-fucosylation of neutral glycans with concurrent decrease of core fucosylation of sialylated glycans.
COCLUSION: The glycan differences among CRC patients are consistent with significantly increased IgG pro-inflammatory activity being associated with poorer CRC prognosis, especially in late stage CRC. Considering the functional relevance of IgG glycosylation for both tumor immunosurveilance and clinical efficacy of therapy with monoclonal antibodies, individual variation in IgG glycosylation may turn out to be important for prediction of disease course or the choice of therapy.

• Keywords: medicine
• Keywords (croatian): medicina
• Language: english
• URN:NBN: urn:nbn:hr:105:632488
• Study programme: Title: Biomedicine and Health Sciences; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstva (doktor/doktorica znanosti, područje biomedicine i zdravstva)
• Type of resource: Text
• Extent: 127 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-05-05 08:22:40