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

Gálvez-Montosa, Fernando; Morelli, Luca; Aoki, Mateus Nobrega; Canzian, Federico; Boggi, Ugo; Kaaks, Rudolf; Gazouli, Maria; Sanchez-Maldonado, José Manuel; Milanetto, Anna Caterina; Uzunoglu, Faik Guntac; Comandatore, Annalisa; Goetz, Mara R; Perri, Francesco; Basso, Daniela; Neoptolemos, John P; Ginocchi, Laura; Landi, Stefano; Zanette, Dalila Luciola; Bueno-de-Mesquita, H Bas; Arcidiacono, Paolo Giorgio; Kupcinskas, Juozas; Ermini, Stefano; Latiano, Anna; Carrara, Silvia; Oliverius, Martin; Peduzzi, Giulia; Izbicki, Jakob R; Tamás, Hussein; Reyes-Zurita, Fernando Jesus; Li, Yang; Pasquali, Claudio; Schöttker, Ben; Netea, Mihai G; Sumskiene, Jolanta; Luchini, Claudio; Dohan, Orsolya; Mohelníková-Duchoňová, Beatrice; Vanella, Giuseppe; Capurso, Gabriele; Archibugi, Livia; Theodoropoulos, George E; Van Laarhoven, Hanneke; Sperti, Cosimo; Szentesi, Andrea; Puzzono, Marta; Lawlor, Rita T; García-Verdejo, Francisco Javier; van Eijck, Casper H J; Luque, Natalia; Macauda, Angelica; Lovecek, Martin; Adamonis, Kestutis; Brenner, Hermann; Hegyi, Péter; Roth, Susanne; Vermeulen, Roel C H; Bunduc, Stefania; Tacelli, Matteo; Sainz, Juan; Pezzilli, Raffaele; Soucek, Pavel; López López, José Antonio; Cabrera-Serrano, Antonio J; Sánchez-Rovira, Pedro; Stein, Angelika; Ünal, Pelin; Lucchesi, Maurizio; Nappo, Gennaro; Talar-Wojnarowska, Renata; Ter Horst, Rob; Greenhalf, William; Kahlert, Christoph; Petrone, Maria Chiara; Campa, Daniele; Gentiluomo, Manuel; Vodickova, Ludmila; Busch, Olivier; Holleczek, Bernd; Cavestro, Giulia Martina; Tavano, Francesca; Petrenkiene, Vitalija

doi:10.1002/ijc.35196

Items
Marc 21

001			293614
005			20250731105425.0
024	7	_	\|a 10.1002/ijc.35196 \|2 doi
024	7	_	\|a pmid:39319538 \|2 pmid
024	7	_	\|a 0020-7136 \|2 ISSN
024	7	_	\|a 1097-0215 \|2 ISSN
024	7	_	\|a altmetric:168826008 \|2 altmetric
037	_	_	\|a DKFZ-2024-01930
041	_	_	\|a English
082	_	_	\|a 610
100	1	_	\|a Gálvez-Montosa, Fernando \|b 0
245	_	_	\|a Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization.
260	_	_	\|a Bognor Regis \|c 2025 \|b Wiley-Liss
336	7	_	\|a article \|2 DRIVER
336	7	_	\|a Output Types/Journal article \|2 DataCite
336	7	_	\|a Journal Article \|b journal \|m journal \|0 PUB:(DE-HGF)16 \|s 1732196233_5932 \|2 PUB:(DE-HGF)
336	7	_	\|a ARTICLE \|2 BibTeX
336	7	_	\|a JOURNAL_ARTICLE \|2 ORCID
336	7	_	\|a Journal Article \|0 0 \|2 EndNote
500	_	_	\|a 2025 Jan 15;156(2):339-352
520	_	_	\|a 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.
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650	_	7	\|a autophagy \|2 Other
650	_	7	\|a functional characterization \|2 Other
650	_	7	\|a genetic variants \|2 Other
650	_	7	\|a pancreatic cancer \|2 Other
650	_	7	\|a polymorphisms \|2 Other
650	_	7	\|a susceptibility \|2 Other
700	1	_	\|a Peduzzi, Giulia \|b 1
700	1	_	\|a Sanchez-Maldonado, José Manuel \|0 P:(DE-HGF)0 \|b 2
700	1	_	\|a Ter Horst, Rob \|b 3
700	1	_	\|a Cabrera-Serrano, Antonio J \|b 4
700	1	_	\|a Gentiluomo, Manuel \|b 5
700	1	_	\|a Macauda, Angelica \|0 P:(DE-He78)b791a47b92809f7c54501331f72e0243 \|b 6 \|u dkfz
700	1	_	\|a Luque, Natalia \|b 7
700	1	_	\|a Ünal, Pelin \|0 P:(DE-He78)0149ac455a0174a847bd30162edf897b \|b 8 \|u dkfz
700	1	_	\|a García-Verdejo, Francisco Javier \|b 9
700	1	_	\|a Li, Yang \|b 10
700	1	_	\|a López López, José Antonio \|b 11
700	1	_	\|a Stein, Angelika \|0 P:(DE-He78)c2ba7331c92b97094f5a95778f3d1940 \|b 12 \|u dkfz
700	1	_	\|a Bueno-de-Mesquita, H Bas \|b 13
700	1	_	\|a Arcidiacono, Paolo Giorgio \|b 14
700	1	_	\|a Zanette, Dalila Luciola \|b 15
700	1	_	\|a Kahlert, Christoph \|b 16
700	1	_	\|a Perri, Francesco \|b 17
700	1	_	\|a Soucek, Pavel \|0 0000-0002-4294-6799 \|b 18
700	1	_	\|a Talar-Wojnarowska, Renata \|b 19
700	1	_	\|a Theodoropoulos, George E \|b 20
700	1	_	\|a Izbicki, Jakob R \|b 21
700	1	_	\|a Tamás, Hussein \|b 22
700	1	_	\|a Van Laarhoven, Hanneke \|b 23
700	1	_	\|a Nappo, Gennaro \|b 24
700	1	_	\|a Petrone, Maria Chiara \|b 25
700	1	_	\|a Lovecek, Martin \|b 26
700	1	_	\|a Vermeulen, Roel C H \|b 27
700	1	_	\|a Adamonis, Kestutis \|b 28
700	1	_	\|a Reyes-Zurita, Fernando Jesus \|b 29
700	1	_	\|a Holleczek, Bernd \|0 P:(DE-He78)53e1a2846c69064e27790dbf349ccaec \|b 30 \|u dkfz
700	1	_	\|a Sumskiene, Jolanta \|b 31
700	1	_	\|a Mohelníková-Duchoňová, Beatrice \|b 32
700	1	_	\|a Lawlor, Rita T \|b 33
700	1	_	\|a Pezzilli, Raffaele \|b 34
700	1	_	\|a Aoki, Mateus Nobrega \|b 35
700	1	_	\|a Pasquali, Claudio \|b 36
700	1	_	\|a Petrenkiene, Vitalija \|b 37
700	1	_	\|a Basso, Daniela \|b 38
700	1	_	\|a Bunduc, Stefania \|b 39
700	1	_	\|a Comandatore, Annalisa \|b 40
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700	1	_	\|a Ermini, Stefano \|b 42
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700	1	_	\|a Goetz, Mara R \|b 44
700	1	_	\|a Archibugi, Livia \|b 45
700	1	_	\|a Lucchesi, Maurizio \|b 46
700	1	_	\|a Uzunoglu, Faik Guntac \|b 47
700	1	_	\|a Busch, Olivier \|b 48
700	1	_	\|a Milanetto, Anna Caterina \|b 49
700	1	_	\|a Puzzono, Marta \|b 50
700	1	_	\|a Kupcinskas, Juozas \|b 51
700	1	_	\|a Morelli, Luca \|b 52
700	1	_	\|a Sperti, Cosimo \|b 53
700	1	_	\|a Carrara, Silvia \|b 54
700	1	_	\|a Capurso, Gabriele \|b 55
700	1	_	\|a van Eijck, Casper H J \|b 56
700	1	_	\|a Oliverius, Martin \|b 57
700	1	_	\|a Roth, Susanne \|b 58
700	1	_	\|a Tavano, Francesca \|0 0000-0002-8831-7349 \|b 59
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700	1	_	\|a Szentesi, Andrea \|b 61
700	1	_	\|a Vodickova, Ludmila \|b 62
700	1	_	\|a Luchini, Claudio \|b 63
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700	1	_	\|a Dohan, Orsolya \|b 66
700	1	_	\|a Tacelli, Matteo \|b 67
700	1	_	\|a Greenhalf, William \|b 68
700	1	_	\|a Gazouli, Maria \|0 0000-0002-3295-6811 \|b 69
700	1	_	\|a Neoptolemos, John P \|b 70
700	1	_	\|a Cavestro, Giulia Martina \|b 71
700	1	_	\|a Boggi, Ugo \|b 72
700	1	_	\|a Latiano, Anna \|b 73
700	1	_	\|a Hegyi, Péter \|b 74
700	1	_	\|a Ginocchi, Laura \|b 75
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Marc 21

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