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Meta-Analysis
. 2025 Jan 15;156(2):339-352.
doi: 10.1002/ijc.35196. Epub 2024 Sep 25.

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

Fernando Gálvez-Montosa  1 , Giulia Peduzzi  2 , José Manuel Sanchez-Maldonado  3   4   5   6 , Rob Ter Horst  7   8 , Antonio J Cabrera-Serrano  4   5 , Manuel Gentiluomo  2 , Angelica Macauda  6 , Natalia Luque  1 , Pelin Ünal  6 , Francisco José García-Verdejo  1 , Yang Li  7   8 , José Antonio López López  1 , Angelika Stein  6 , H Bas Bueno-de-Mesquita #  9 , Paolo Giorgio Arcidiacono  10 , Dalila Luciola Zanette  11 , Christoph Kahlert  12 , Francesco Perri  13 , Pavel Soucek  14 , Renata Talar-Wojnarowska  15 , George E Theodoropoulos  16 , Jakob R Izbicki  17 , Hussein Tamás  18   19 , Hanneke Van Laarhoven  20   21 , Gennaro Nappo  22   23 , Maria Chiara Petrone  10 , Martin Lovecek  24 , Roel C H Vermeulen  25 , Kestutis Adamonis  26 , Fernando Jesus Reyes-Zurita  3 , Bernd Holleczek  27   28 , Jolanta Sumskiene  26 , Beatrice Mohelníková-Duchoňová  29 , Rita T Lawlor  30   31 , Raffaele Pezzilli  32 , Mateus Nobrega Aoki  11 , Claudio Pasquali  33 , Vitalija Petrenkiene  26 , Daniela Basso  34 , Stefania Bunduc  18   19   35   36 , Annalisa Comandatore  37 , Hermann Brenner  28   38 , Stefano Ermini  2 , Giuseppe Vanella  39   40 , Mara R Goetz  17 , Livia Archibugi  39   40 , Maurizio Lucchesi  41 , Faik Guntac Uzunoglu  17 , Olivier Busch  21   42 , Anna Caterina Milanetto  33 , Marta Puzzono  43 , Juozas Kupcinskas  26 , Luca Morelli  37 , Cosimo Sperti  33 , Silvia Carrara  44 , Gabriele Capurso  39   40 , Casper H J van Eijck  45 , Martin Oliverius  46 , Susanne Roth  12 , Francesca Tavano  13 , Rudolf Kaaks  47 , Andrea Szentesi  48 , Ludmila Vodickova  49   50   51 , Claudio Luchini  30   52 , Ben Schöttker  28 , Stefano Landi  2 , Orsolya Dohan  19 , Matteo Tacelli  10 , William Greenhalf  53 , Maria Gazouli  54 , John P Neoptolemos  12 , Giulia Martina Cavestro  43 , Ugo Boggi  55 , Anna Latiano  13 , Péter Hegyi  18   19   48   56 , Laura Ginocchi  41 , Mihai G Netea  57   58 , Pedro Sánchez-Rovira  1 , Federico Canzian  6 , Daniele Campa  2 , Juan Sainz  3   4   5   59
Affiliations
Meta-Analysis

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

Fernando Gálvez-Montosa et al. Int J Cancer. .

Erratum in

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 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.

Keywords: autophagy; functional characterization; genetic variants; pancreatic cancer; polymorphisms; susceptibility.

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Conflict of interest statement

All authors have no competing interests to disclose.

Figures

FIGURE 1
FIGURE 1
Flow diagram of the study.
FIGURE 2
FIGURE 2
(A–C) Correlation of the TP63 rs1515496 SNP with numbers of specific T regulatory T cell subsets.
See this image and copyright information in PMC

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