A glycosyltransferase gene signature to detect pancreatic ductal adenocarcinoma patients with poor prognosis

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an important heterogeneity, reflected by different clinical outcomes and chemoresistance. During carcinogenesis, tumor cells display aberrant glycosylated structures, synthetized by deregulated glycosyltransferases, supporting the tumor pro-gression. In this study, we aimed to determine whether PDAC could be stratified through their glycosyltrans-ferase expression profiles better than the current binary classification (basal-like and classical) in order to improve detection of patients with poor prognosis. Methods: Bioinformatic analysis of 169 glycosyltransferase RNA sequencing data were performed for 74 patient-derived xenografts (PDX) of resected and unresectable tumors. The Australian cohort of International Cancer Genome Consortium and the microarray dataset from Puleo patient's cohort were used as indepen-dent validation datasets. Findings: New PDAC stratification based on glycosyltransferase expression profile allowed to distinguish dif-ferent groups of patients with distinct clinical outcome (p-value = 0.007). A combination of 19 glycosyltrans-ferases differentially expressed in PDX defined a glyco-signature, whose prognostic value was validated on datasets including resected whole tumor tissues. The glyco-signature was able to discriminate three clusters of PDAC patients on the validation cohorts, two clusters displaying a short overall survival compared to one cluster having a better prognosis. Both poor prognostic clusters having different glyco-profiles in Puleo patient's cohort were correlated with stroma activated or desmoplastic subtypes corresponding to distinct microenvironment features (p-value < 0.0001). Besides, differential expression and enrichment analyses revealed deregulated functional pathways specific to different clusters. Interpretation: This study identifies a glyco-signature relevant for a prognostic use, potentially applicable to resected and unresectable PDAC. Furthermore, it provides new potential therapeutic targets. Funding: This work was supported by INCa (Grants number 2018-078 and 2018-079), Fondation ARC (Grant number ARCPJA32020070002326), Canc = eropo<^>le PACA, DGOS (labelization SIRIC, Grant number 6038), Ami-dex Foundation and Ligue Nationale Contre le Cancer and by institutional fundings from INSERM and the Aix-Marseille Universit = e. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Automated summary

The study identified a novel stratification of PDAC based on glycosyltransferase expression profiles, showing distinct clinical outcomes with prognostic value. This glyco-signature may serve as a potential prognostic tool and offer new therapeutic targets for resected and unresectable PDAC patients.