000293614 001__ 293614 000293614 005__ 20250731105425.0 000293614 0247_ $$2doi$$a10.1002/ijc.35196 000293614 0247_ $$2pmid$$apmid:39319538 000293614 0247_ $$2ISSN$$a0020-7136 000293614 0247_ $$2ISSN$$a1097-0215 000293614 0247_ $$2altmetric$$aaltmetric:168826008 000293614 037__ $$aDKFZ-2024-01930 000293614 041__ $$aEnglish 000293614 082__ $$a610 000293614 1001_ $$aGálvez-Montosa, Fernando$$b0 000293614 245__ $$aPolymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization. 000293614 260__ $$aBognor Regis$$bWiley-Liss$$c2025 000293614 3367_ $$2DRIVER$$aarticle 000293614 3367_ $$2DataCite$$aOutput Types/Journal article 000293614 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1732196233_5932 000293614 3367_ $$2BibTeX$$aARTICLE 000293614 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000293614 3367_ $$00$$2EndNote$$aJournal Article 000293614 500__ $$a2025 Jan 15;156(2):339-352 000293614 520__ $$aPancreatic 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. 000293614 536__ $$0G:(DE-HGF)POF4-313$$a313 - Krebsrisikofaktoren und Prävention (POF4-313)$$cPOF4-313$$fPOF IV$$x0 000293614 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de 000293614 650_7 $$2Other$$aautophagy 000293614 650_7 $$2Other$$afunctional characterization 000293614 650_7 $$2Other$$agenetic variants 000293614 650_7 $$2Other$$apancreatic cancer 000293614 650_7 $$2Other$$apolymorphisms 000293614 650_7 $$2Other$$asusceptibility 000293614 7001_ $$aPeduzzi, Giulia$$b1 000293614 7001_ $$0P:(DE-HGF)0$$aSanchez-Maldonado, José Manuel$$b2 000293614 7001_ $$aTer Horst, Rob$$b3 000293614 7001_ $$aCabrera-Serrano, Antonio J$$b4 000293614 7001_ $$aGentiluomo, Manuel$$b5 000293614 7001_ $$0P:(DE-He78)b791a47b92809f7c54501331f72e0243$$aMacauda, Angelica$$b6$$udkfz 000293614 7001_ $$aLuque, Natalia$$b7 000293614 7001_ $$0P:(DE-He78)0149ac455a0174a847bd30162edf897b$$aÜnal, 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