The PANcreatic Disease ReseArch (PANDoRA) consortium: Ten years’ experience of association studies to understand the genetic architecture of pancreatic cancer

Campa, Daniele; Gentiluomo, Manuel; Stein, Angelika; Aoki, Mateus Nóbrega; Oliverius, Martin; Vodičková, Ludmila; Jamroziak, Krzysztof; Theodoropoulos, George; Pasquali, Claudio; Greenhalf, William; Arcidiacono, Paolo Giorgio; Uzunoglu, Faik; Pezzilli, Raffaele; Luchini, Claudio; Puzzono, Marta; Loos, Martin; Giaccherini, Matteo; Katzke, Verena; Mambrini, Andrea; Kiudeliene, Edita; Federico, Kauffmann Emanuele; Johansen, Julia; Hussein, Tamás; Mohelnikova-Duchonova, Beatrice; van Eijck, Casper H.J.; Brenner, Hermann; Farinella, Riccardo; Pérez, Juan Sainz; Lovecek, Martin; Büchler, Markus W.; Hlavac, Viktor; Izbicki, Jakob R.; Hackert, Thilo; Chammas, Roger; Zerbi, Alessandro; Lawlor, Rita; Felici, Alessio; Götz, Mara; Capurso, Gabriele; Ginocchi, Laura; Gazouli, Maria; Kupcinskas, Juozas; Cavestro, Giulia Martina; Vodicka, Pavel; Moz, Stefania; Neoptolemos, John P.; Kunovsky, Lumir; Bojesen, Stig E.; Carrara, Silvia; Gioffreda, Domenica; Morkunas, Egidijus; Abian, Olga; Bunduc, Stefania; Basso, Daniela; Boggi, Ugo; Wlodarczyk, Barbara; Szentesi, Andrea; Vanella, Giuseppe; Chen, Inna; Bijlsma, Maarten F.; Kiudelis, Vytautas; Landi, Stefano; Schöttker, Ben; Corradi, Chiara; Giese, Nathalia; Kaaks, Rudolf; Peduzzi, Giulia; Hegyi, Péter; Morelli, Luca; Furbetta, Niccolò; Soucek, Pavel; Latiano, Anna; Talar-Wojnarowska, Renata; Lindgaard, Sidsel C.; Dijk, Frederike; Milanetto, Anna Caterina; Tavano, Francesca; Cervena, Klara; Erőss, Bálint; Testoni, Sabrina G.; Verhagen-Oldenampsen, Judith H.E.; Małecka-Wojciesko, Ewa; Costello, Eithne; Salvia, Roberto; Maiello, Evaristo; Ermini, Stefano; Sperti, Cosimo; Holleczek, Bernd; Perri, Francesco; Skieceviciene, Jurgita; Archibugi, Livia; Lucchesi, Maurizio; Rizzato, Cosmeri; Canzian, Federico

doi:10.1016/j.critrevonc.2023.104020

Cited by 9 publications

(2 citation statements)

References 63 publications

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“…The replication of aSNPs with a P-value of association with PDAC risk lower than the Bonferroni-adjusted threshold (see below) was attempted in the Pancreatic Disease Research (PANDoRA) consortium [ 64 , 65 ]. PANDoRA is a multicentric study on pancreatic cancer based mainly on European countries (Greece, Italy, Germany, Netherlands, Denmark, Czech Republic, Hungary, Poland, Ukraine, Lithuania, UK).…”

Section: Methodsmentioning

confidence: 99%

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians

et al. 2023

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Background The genomes of present-day non-Africans are composed of 1–3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50–60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. Results The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19–1.54, P = 3.59 × 10–6), with a P-value close to a threshold that takes into account multiple testing. Conclusions Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

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Section: Methodsmentioning

confidence: 99%

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians

et al. 2023

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“…One strategy for reducing the number of tests is to examine SNPs with higher prior probability of association according to meaningful biological criteria. We looked for novel MM risk loci using a two-phase large-scale association study, prioritizing polymorphisms with predicted functional impact, a strategy that has been used for other cancers and led to the discovery of new loci [ 5 – 7 ] It is well known that functional variants are indeed more likely to be associated with disease development [ 8 ].…”

Section: To the Editormentioning

confidence: 99%

Identification of novel genetic loci for risk of multiple myeloma by functional annotation

Macauda,

Briem,

Clay-Gilmour

et al. 2023

Leukemia

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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

Gálvez‐Montosa,

Peduzzi,

Sanchez‐Maldonado

et al. 2024

Intl Journal of Cancer

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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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The PANcreatic Disease ReseArch (PANDoRA) consortium: Ten years’ experience of association studies to understand the genetic architecture of pancreatic cancer

Cited by 9 publications

References 63 publications

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians

Identification of novel genetic loci for risk of multiple myeloma by functional annotation

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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