Lack of association of CD44-rs353630 and CHI3L2-rs684559 with pancreatic ductal adenocarcinoma survival

Manuel Gentiluomo,Péter Hegyi,Inna M Chen,Astrid Z Johansen,Carsten Palnæs Hansen,Oliver Strobel,Anna Caterina Milanetto,Dania Bozzato,John P Neoptolemos,Renata Talar-Wojnarowska,Pavel Vodička ,Juozas Kupčinskas ,Pavel Souček ,Beatrice Mohelníková-Duchoňová ,Andrea Szentesi,Paolo Giorgio Arcidiacono,Giulia Martina Cavestro,Giuseppe Vanella,Erika Darvasi,Liliana Piredda,Thilo Hackert,Casper H.j Van Eijck ,Chiara Corradi,Eithne Costello,Raffaele Pezzilli,Francesca Tavano,Maria Gazouli,Federico Canzian,Daniele Campa,Gabriele Capurso

doi:10.1038/s41598-021-87130-0

Abstract

Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients’ response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PANDoRA) consortium. We also analysed the combined effect of the two genotypes in order to compare our results with what was previously reported. Additional stratified analyses considering TNM stage of the disease and whether the patients received surgery were also performed. We observed no statistically significant associations, except for the heterozygous carriers of CD44-rs353630, who were associated with worse OS (HR = 5.01; 95% CI 1.58–15.88; p = 0.006) among patients with stage I disease. This association is in the opposite direction of those reported previously, suggesting that data obtained in such small subgroups are hardly replicable and should be considered cautiously. The two polymorphisms combined did not show any statistically significant association. Our results suggest that the effect of CD44-rs353630 and CHI3L2-rs684559 cannot be generalized to all PDAC patients.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients’ response to the treatments
A small-scale genome-wide association studies (GWAS) done on 252 pancreatic ductal adenocarcinoma (PDAC) cases, with subsequent validation done on 261 and 572 sets of patients, respectively, reported an association between a single nucleotide polymorphism (SNP) on chromosome 12 and overall survival (OS) of PDAC cases (p = 1.72 × 10−7 in the combined dataset)[27]
In one of the few studies of this kind, we genotyped 44 SNPs proposed by the GWAS by Wu et al in one of the largest study so far consisting in 1722 PDAC cases, in the context of the PANDoRA c onsortium[25]

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients’ response to the treatments. Several germline mutations, associated with well described hereditary syndromes, increase the risk of developing PDAC and subjects carrying such mutations are offered surveillance in the context of research p rotocols[5] Besides these high penetrance germline mutations, there are overwhelming evidences on the role of germline genetic polymorphisms in the development of the disease, identified through genome-wide association studies (GWAS) or through large scale case–control studies[6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21]. The lack of replicability of the PDAC survival loci is in striking contrast with the situation observed for GWAS-identified risk loci, which are generally confirmed in multiple independent studies, to some extent even in populations of diverse ethnic background

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