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Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization.

International journal of cancer

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

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BID variant with an increased risk of developing the disease (OR = 1.31, p = 9.67 × 10). We also confirmed the association of TP63 and TP63 variants with PDAC risk (OR = 0.89, p = 6.27 × 10 and OR = 1.16, p = 2.74 × 10). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63 allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10 and p = 1.56 × 10), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10). These results were in agreement with research suggesting that the TP63 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

PMID: 39319538

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