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

Fernando Gálvez; Giulia Peduzzi; José Manuel Sánchez‐Maldonado; Rob ter Horst; Antonio José Cabrera-Serrano; Manuel Gentiluomo; Angelica Macauda; Natalia Luque; Pelin Gürkan Ünal; Francisco José García‐Verdejo; Yang Li; José Antonio López López; Angelika Stein; H. Bas Bueno‐de‐Mesquita; Paolo Giorgio Arcidiacono; Dalila Lucíola Zanette; Christoph Kahlert; Francesco Perri; Pavel Souček; Renata Talar‐Wojnarowska; George Theodoropoulos; Jakob R. Izbicki; Hussein Tamás; Hanneke W.M. van Laarhoven; Gennaro Nappo; Maria Chiara Petrone; Martin Loveček; Roel Vermeulen; Kęstutis Adamonis; Fernando J. Reyes‐Zurita; Bernd Holleczek; Jolanta Šumskienė; B. Mohelníková-Duchoňová; Rita T. Lawlor; Raffaele Pezzilli; Mateus Nóbrega Aoki; Claudio Pasquali; Vitalija Petrenkienė; Daniela Basso; Ștefania Bunduc; Annalisa Comandatore; Hermann Brenner; Stefano Ermini; Giuseppe Vanella; Mara Göetz; Lívia Archibugi; M Lucchesi; Faik G. Uzunoğlu; Olivier R. Busch; Anna Caterina Milanetto; Marta Puzzono; Juozas Kupčinskas; Luca Morelli; Cosimo Sperti; Silvia Carrara; Gabriele Capurso; Casper H.J. van Eijck; Martin Oliverius; Susanne Roth; Francesca Tavano; Rudolf Kaaks; Andrea Szentesi; Ľudmila Vodičková; Claudio Luchini; Ben Schöttker; Stefano Landi; Orsolya Dohán; 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 Sáinz

doi:10.1002/ijc.35196

Hermann Brenner

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Fernando Gálvez

Giulia Peduzzi

José Manuel Sánchez‐Maldonado

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Abstract

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.

How to cite this publication

Fernando Gálvez, Giulia Peduzzi, José Manuel Sánchez‐Maldonado, Rob ter Horst, Antonio José Cabrera-Serrano, Manuel Gentiluomo, Angelica Macauda, Natalia Luque, Pelin Gürkan Ünal, Francisco José García‐Verdejo, Yang Li, José Antonio López López, Angelika Stein, H. Bas Bueno‐de‐Mesquita, Paolo Giorgio Arcidiacono, Dalila Lucíola Zanette, Christoph Kahlert, Francesco Perri, Pavel Souček, Renata Talar‐Wojnarowska, George Theodoropoulos, Jakob R. Izbicki, Hussein Tamás, Hanneke W.M. van Laarhoven, Gennaro Nappo, Maria Chiara Petrone, Martin Loveček, Roel Vermeulen, Kęstutis Adamonis, Fernando J. Reyes‐Zurita, Bernd Holleczek, Jolanta Šumskienė, B. Mohelníková-Duchoňová, Rita T. Lawlor, Raffaele Pezzilli, Mateus Nóbrega Aoki, Claudio Pasquali, Vitalija Petrenkienė, Daniela Basso, Ștefania Bunduc, Annalisa Comandatore, Hermann Brenner, Stefano Ermini, Giuseppe Vanella, Mara Göetz, Lívia Archibugi, M Lucchesi, Faik G. Uzunoğlu, Olivier R. Busch, Anna Caterina Milanetto, Marta Puzzono, Juozas Kupčinskas, Luca Morelli, Cosimo Sperti, Silvia Carrara, Gabriele Capurso, Casper H.J. van Eijck, Martin Oliverius, Susanne Roth, Francesca Tavano, Rudolf Kaaks, Andrea Szentesi, Ľudmila Vodičková, Claudio Luchini, Ben Schöttker, Stefano Landi, Orsolya Dohán, 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 Sáinz (2024). Polymorphisms within autophagy‐related genes as susceptibility biomarkers for pancreatic cancer: A meta‐analysis of three large European cohorts and functional characterization. , 156(2), DOI: https://doi.org/10.1002/ijc.35196.

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

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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

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