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

• Published in: International journal of cancer Vol. 156; no. 2; pp. 339 - 352
• Main Authors: Gálvez‐Montosa, Fernando, Peduzzi, Giulia, Sanchez‐Maldonado, José Manuel, ter Horst, Rob, Cabrera‐Serrano, Antonio J., Gentiluomo, Manuel, Macauda, Angelica, Luque, Natalia, Ünal, Pelin, García‐Verdejo, Francisco José, Li, Yang, López López, José Antonio, Stein, Angelika, Bueno‐de‐Mesquita, H. Bas, Arcidiacono, Paolo Giorgio, Zanette, Dalila Luciola, Kahlert, Christoph, Perri, Francesco, Soucek, Pavel, Talar‐Wojnarowska, Renata, Theodoropoulos, George E., Izbicki, Jakob R., Tamás, Hussein, Van Laarhoven, Hanneke, Nappo, Gennaro, Petrone, Maria Chiara, Lovecek, Martin, Vermeulen, Roel C. H., Adamonis, Kestutis, Reyes‐Zurita, Fernando Jesus, Holleczek, Bernd, Sumskiene, Jolanta, Mohelníková‐Duchoňová, Beatrice, Lawlor, Rita T., Pezzilli, Raffaele, Aoki, Mateus Nobrega, 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 Guntac, Busch, Olivier, Milanetto, Anna Caterina, Puzzono, Marta, Kupcinskas, Juozas, Morelli, Luca, Sperti, Cosimo, Carrara, Silvia, Capurso, Gabriele, van Eijck, Casper H. J., 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., Sánchez‐Rovira, Pedro, Canzian, Federico, Campa, Daniele, Sainz, Juan
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.01.2025; John Wiley & Sons, Inc
• Subjects: Adenocarcinoma; Autophagy; Autophagy - genetics; Biomarkers, Tumor - genetics; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Case-Control Studies; CD4 antigen; CD45RA antigen; Cohort Studies; Forkhead Transcription Factors; Foxp3 protein; Genetic diversity; Genetic Predisposition to Disease; Hepatocyte Nuclear Factor 3-alpha - genetics; Hepatocyte Nuclear Factor 3-alpha - metabolism; Humans; Immunoregulation; Lymphocytes T; Medical prognosis; Meta-analysis; Metastases; Metastasis; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Polymorphism, Single Nucleotide; RESEARCH ARTICLE; Single-nucleotide polymorphism; Susceptibility; Transcription factors; Transcription Factors - genetics; Tumor Suppressor Proteins - genetics; White People - genetics; genetic variants; pancreatic cancer; autophagy; susceptibility; polymorphisms; functional characterization
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.35196

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 rs9604789 variant with an increased risk of developing the disease (OR Meta = 1.31, p = 9.67 × 10 −6 ). We also confirmed the association of TP63 rs1515496 and TP63 rs35389543 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 TP63 rs1515496G 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 TP63 rs1515496 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.