Author
Affilliation
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 10E-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 x 10E-8 and OR = 1.16, p = 2.74 x 10E-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 x 10E-4 and p = 1.56 x 10E-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 x 10E-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.
Publisher
WILEY
Citation
GÁLVEZ-MONTOSA, F. et al. Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: a metaanalysis of three large European cohorts and functional characterization. International Journal of Cancer, v. 156, n. 2, p. 339-352, 2024.
DOI
10.1002/ijc.35196
ISSN
1097-0215
Notes
Afiliações
1 - Complejo Hospitalario de Jaén. Department of Medical Oncology. Jaén, Spain.
2 - University of Pisa. Department of Biology. Pisa, Italy.
3 - University of Granada. Department of Biochemistry and Molecular Biology I. Granada, Spain.
4 - Andalusian Regional Government. University of Granada. Genomic Oncology Area. Centre for Genomics and Oncological Research: Pfizer. Granada, Spain.
5 - Instituto de Investigación Biosanataria Ibs. Granada, Granada, Spain.
6 - German Cancer Research Center. Genomic Epidemiology Group. Heidelberg, Germany.
7 - Radboud University Medical Center. Department of Internal Medicine and Radboud Center for Infectious Diseases, Nijmegen, The Netherlands.
8 - CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Vienna, Austria.
9 - National Institute for Public Health and the Environment. Bilthoven, The Netherlands.
10 - San Raffaele Scientific Institute. Pancreas Translational & Clinical Research Center. Pancreatico/Biliary Endoscopy & Endosonography Division. Milan, Italy.
11 - Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Ciências e Tecnologias Aplicadas em Saúde. Curitiba, PR, Brasil.
12 - University of Heidelberg. Department of General Surgery. Heidelberg, Baden-Württemberg, Germany.
13 - Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital. Division of Gastroenterology and Research Laboratory. Foggia, Italy.
14 - Charles University. Faculty of Medicine in Pilsen. Biomedical Center. Pilsen, Czech Republic.
15 - Medical University of Lodz. Department of Digestive Tract Diseases. Lodz, Poland.
16 - Medical School of National and Kapodistrian University of Athens. Hippocration General Hospital. First Department of Propaedeutic Surgery. Colorectal Unit. Athens, Greece
17 - University Medical Center Hamburg-Eppendorf. Department of General, Visceral and Thoracic Surgery. Hamburg, Germany.
18 - Semmelweis University. Center for Translational Medicine. Budapest, Hungary.
19 - Semmelweis University. Heart and Vascular Center. Division of Pancreatic Diseases. Budapest, Hungary.
20 - Amsterdam UMC location. University of Amsterdam. Department of Medical Oncology. Amsterdam, The Netherlands.
21 - Cancer Center Amsterdam, Imaging and Biomarkers. Amsterdam, The Netherlands.
22 - IRCCS Humanitas Research Hospital. Pancreatic Unit. Milan, Italy.
23 - Humanitas University. Department of Biomedical Sciences. Milan, Italy.
24 - University Hospital Olomouc. Department of Surgery I. Olomouc, Czech Republic.
25 - University of Utrecht. Utrecht, The Netherlands.
26 - Lithuanian University of Health Sciences. Gastroenterology Department and Institute for Digestive Research. Kaunas, Lithuania.
27 - Saarland Cancer Registry. Saarbrücken, Germany.
28 - German Cancer Research Center (DKFZ). Division of Clinical Epidemiology and Aging Research. Heidelberg, Germany.
29 - National Institute of Public Health. Toxicogenomics Unit. Prague, Czech Republic.
30 - University of Verona. ARC-Net Centre for Applied Research on Cancer. Verona, Italy.
31 - University of Verona. Department of Diagnostics and Public Health. Section of Pathology. Verona, Italy.
32 - Potenza County Medical Association. Potenza, Italy.
33 - University of Padova. Department of DISCOG. Padova, Italy.
34 - University of Padova. Department of DIMED. Laboratory Medicine. Padova, Italy.
35 - Carol Davila University of Medicine and Pharmacy. Bucharest, Romania.
36 - Fundeni Clinical Institute. Digestive Diseases and Liver Transplantation Center. Bucharest, Romania.
37 - University of Pisa. General Surgery Unit, Department of Translational Research and New Technologies in Medicine. Pisa, Italy.
38 - German Cancer Consortium (DKTK). German Cancer Research Center (DKFZ). Heidelberg, Germany.
39 - S Andrea Hospital. Digestive and Liver Disease Unit. Rome, Italy.
40 - San Raffaele Scientific Institute IRCCS. Pancreas Translational and Clinical Research Center. Pancreato Biliary Endoscopy and Endoscopic Ultrasound. Milan, Italy.
41 - Oncologia Massa Carrara. Azienda USL Toscana Nord Ovest. Carrara, Italy.
42 - Amsterdam UMC Location. University of Amsterdam. Department of Medical Oncology. Amsterdam, The Netherlands.
43 - Vita-Salute San Raffaele University. IRCCS San Raffaele Scientific Institute. Gastroenterology and Gastrointestinal Endoscopy Unit. Milan, Italy.
44 - IRCCS Humanitas Research Hospital. Department of Gastroenterology. Endoscopic Unit. Milan, Italy.
45 - Erasmus MC University Medical Center. Department of Surgery. Rotterdam, The Netherlands.
46 - Charles University. University Hospital Kralovske Vinohrady. Third Faculty of Medicine. Department of Surgery. Prague, Czech Republic.
47 - German Cancer Research Center (DKFZ). Division of Cancer Epidemiology. Heidelberg, Germany.
48 - University of Pécs. Institute for Translational Medicine. Medical School. Pécs, Hungary.
49 - Institute of Experimental Medicine. Czech Academy of Sciences. Department of Molecular Biology of Cancer. Prague, Czech Republic.
50 - Charles University. Institute of Biology and Medical Genetics. First Faculty of Medicine. Prague, Czech Republic.
51 - Charles University. Faculty of Medicine and Biomedical Center in Pilsen. Pilsen, Czech Republic.
52 - University of Verona. Department of Engineering for Innovation in Medicine. Verona, Italy.
53 - University of Liverpool. Institute for Health Research Liverpool Pancreas Biomedical Research Unit. Liverpool, United Kingdom.
54 - National and Kapodistrian University of Athens. Medical School. Department of Basic Medical Science. Laboratory of Biology. Athens, Greece.
55 - Pisa University Hospital. Division of General and Transplant Surgery. Pisa, Italy.
56 - University of Pécs. János Szentágothai Research Center. Pécs, Hungary.
57 - Centre for Individualised Infection Medicine (CiiM) & TWINCORE. Helmholtz-Centre for Infection Research (HZI). Hannover Medical School (MHH). Hannover, Germany.
58 - University of Bonn. Life and Medical Sciences Institute. Department for Immunology & Metabolism. Bonn, Germany.
59 - Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP). Barcelona, Spain.
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