Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: a meta-analysis of four large European cohorts and functional characterization
Authors: Gálvez-Montosa Fernando , Peduzzi Giulia , Sanchez-Maldonado José Manuel , Horst Rob Ter , Cabrera-Serrano Antonio José , Gentiluomo Manuel , Macauda Angelica , Luque Natalia , Ünal Pelin , García-Verdejo Francisco José , Li Yang , López-Lopez José Antonio , Stein Angelika , Bueno-de-Mesquita Bas , Arcidiacono Paolo Giorgio , Zanette Dalila Lucíola , Kahlert Christoph , Perri Francesco , Soucek Pavel , Talar-Wojnarowska Renata , Theodoropoulos George , Izbicki Jakob R. , Hussein Tamás , Laarhoven Hanneke Van , Nappo Gennaro , Petrone Maria Chiara , Lovecek Martin , Vermeulen Roel C.H. , Adamonis Kestutis , Holleczek Bernd , Sumskiene Jolanta , Mohelnikova-Duchonova Beatrice , Lawlor Rita T. , Pezzilli Raffaele , Aoki Mateus Nóbrega , Pasquali Claudio , Petrenkiene Vitalija , Basso Daniela , Bunduc Stefania , Comandatore Annalisa , Brenner Hermann , Ermini Stefano , Vanella Giuseppe , Goetz Mara R. , Archibugi Livia , Lucchesi Maurizio , Uzunoglu Faik G. , Busch Olivier , Milanetto Anna Caterina , Puzzono Marta , Kupcinskas Juozas , Morelli Luca , Sperti Cosimo , Carrara Silvia , Capurso Gabriele , Eijck Casper H J Van , Oliverius Martin , Roth Susanne , Tavano Francesca , Kaaks Rudolf , Szentesi Andrea , Vodickova Ludmila , Luchini Claudio , Schöttker Ben , Landi Stefano , Dohan Orsolya , Tacelli Matteo , Greenhalf William , Gazouli Maria , Neoptolemos John P , Cavestro Giulia Martina , Boggi Ugo , Latiano Anna , Hegyi Péter , Ginocchi Laura , Netea Mihai G. , Sanchez-Rovira Pedro , Canzian Federico , Campa Daniele , Sainz Juan 
Published: December 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. The vast majority of patients have unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Considering this fact, it is urgent to understand the genetic basis of susceptibility to PDAC and to develop more individualized prevention strategies. For that purpose, we comprehensively investigated whether 55,583 genetic variants within 234 autophagy-related genes could influence the risk of developing PDAC in three large and independent cohorts of European ancestry including 13,215 PDAC cases and 270,274 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta=1.28, 95%CI 1.13–1.46, p = 1.47 ×10− 4) and validated the association of previously reported susceptibility variants for PDAC (TP63rs1515496, OR = 0.88, p = 8.43×10− 9; TP53rs35850753, OR = 0.77, p = 2.50×10− 4). At functional level, we found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3 + Helios + T regulatory cells and CD45RA + T regulatory cells (p = 7.67×10− 4 and p = 1.56×10− 3, respectively), but also decreased levels of CD4 + T regulatory cells (p = 7.86×10− 4). Although none of these results remain significant using a multiple testing corrected threshold (pBonferroni=2.11×10− 5), they are in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, transcription factors involved in the modulation of regulatory T cells. In conclusion, this study validated the association of single nucleotide polymorphisms (SNPs) within the TP53 and TP63 loci with PDAC risk and suggested, for the first time, that the BIDrs9604789 SNP is a new susceptibility marker for PDAC. Functional experiments suggested that the TP63 locus might influence the risk of PDAC by modulating the number of specific T regulatory subsets.