TY  - JOUR
AU  - Gálvez-Montosa, Fernando
AU  - Peduzzi, Giulia
AU  - Sanchez-Maldonado, José Manuel
AU  - Ter Horst, Rob
AU  - Cabrera-Serrano, Antonio J
AU  - Gentiluomo, Manuel
AU  - Macauda, Angelica
AU  - Luque, Natalia
AU  - Ünal, Pelin
AU  - García-Verdejo, Francisco Javier
AU  - Li, Yang
AU  - López López, José Antonio
AU  - Stein, Angelika
AU  - Bueno-de-Mesquita, H Bas
AU  - Arcidiacono, Paolo Giorgio
AU  - Zanette, Dalila Luciola
AU  - Kahlert, Christoph
AU  - Perri, Francesco
AU  - Soucek, Pavel
AU  - Talar-Wojnarowska, Renata
AU  - Theodoropoulos, George E
AU  - Izbicki, Jakob R
AU  - Tamás, Hussein
AU  - Van Laarhoven, Hanneke
AU  - Nappo, Gennaro
AU  - Petrone, Maria Chiara
AU  - Lovecek, Martin
AU  - Vermeulen, Roel C H
AU  - Adamonis, Kestutis
AU  - Reyes-Zurita, Fernando Jesus
AU  - Holleczek, Bernd
AU  - Sumskiene, Jolanta
AU  - Mohelníková-Duchoňová, Beatrice
AU  - Lawlor, Rita T
AU  - Pezzilli, Raffaele
AU  - Aoki, Mateus Nobrega
AU  - Pasquali, Claudio
AU  - Petrenkiene, Vitalija
AU  - Basso, Daniela
AU  - Bunduc, Stefania
AU  - Comandatore, Annalisa
AU  - Brenner, Hermann
AU  - Ermini, Stefano
AU  - Vanella, Giuseppe
AU  - Goetz, Mara R
AU  - Archibugi, Livia
AU  - Lucchesi, Maurizio
AU  - Uzunoglu, Faik Guntac
AU  - Busch, Olivier
AU  - Milanetto, Anna Caterina
AU  - Puzzono, Marta
AU  - Kupcinskas, Juozas
AU  - Morelli, Luca
AU  - Sperti, Cosimo
AU  - Carrara, Silvia
AU  - Capurso, Gabriele
AU  - van Eijck, Casper H J
AU  - Oliverius, Martin
AU  - Roth, Susanne
AU  - Tavano, Francesca
AU  - Kaaks, Rudolf
AU  - Szentesi, Andrea
AU  - Vodickova, Ludmila
AU  - Luchini, Claudio
AU  - Schöttker, Ben
AU  - Landi, Stefano
AU  - Dohan, Orsolya
AU  - Tacelli, Matteo
AU  - Greenhalf, William
AU  - Gazouli, Maria
AU  - Neoptolemos, John P
AU  - Cavestro, Giulia Martina
AU  - Boggi, Ugo
AU  - Latiano, Anna
AU  - Hegyi, Péter
AU  - Ginocchi, Laura
AU  - Netea, Mihai G
AU  - Sánchez-Rovira, Pedro
AU  - Canzian, Federico
AU  - Campa, Daniele
AU  - Sainz, Juan
TI  - Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization.
JO  - International journal of cancer
VL  - 156
IS  - 2
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2024-01930
SP  - 339-352
PY  - 2025
N1  - 2025 Jan 15;156(2):339-352
AB  - 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 BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also 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), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 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.
KW  - autophagy (Other)
KW  - functional characterization (Other)
KW  - genetic variants (Other)
KW  - pancreatic cancer (Other)
KW  - polymorphisms (Other)
KW  - susceptibility (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39319538
DO  - DOI:10.1002/ijc.35196
UR  - https://inrepo02.dkfz.de/record/293614
ER  -