Pancreatic cancer (PC), particularly pancreatic ductal adenocarcinoma (PDAC), is a significant global health issue with high mortality rates. PDAC, though only 3 % of cancer diagnoses, causes 7 % of cancer deaths due to its severity and asymptomatic early stages. Risk factors include lifestyle choices, environmental exposures, and genetic predispositions. Conditions like new-onset type 2 diabetes and chronic pancreatitis also contribute significantly. Modifiable risk factors include smoking, alcohol consumption, non-alcoholic fatty pancreatic disease (NAFPD), and obesity. Smoking and heavy alcohol consumption increase PC risk, while NAFPD and obesity, particularly central adiposity, contribute through chronic inflammation and insulin resistance. Refined sugar and sugar-sweetened beverages (SSBs) are also linked to increased PC risk, especially among younger individuals. Hormonal treatments and medications like statins, aspirin, and metformin have mixed results on PC risk, with some showing protective effects. The gut microbiome influences PC through the gut-pancreas axis, with disruptions leading to inflammation and carcinogenesis. Exposure to toxic substances, including heavy metals and chemicals, is associated with increased PC risk. Glycome changes, such as abnormal glycosylation patterns, are significant in PDAC development and offer potential for early diagnosis. Interactions between environmental and genetic factors are crucial in PDAC susceptibility. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) linked to PDAC, but gene-environment interactions remain largely unexplored. Future research should focus on polygenic risk scores (PRS) and large-scale studies to better understand these interactions and their impact on PDAC risk.

Biomedical Center Martin Bioinformatic Center Comenius University in Bratislava Jessenius Faculty of Medicine in Martin Slovakia; Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

Cancer Mechanisms and Biomarkers Research Group School of Life Sciences University of Westminster London UK

Chair of Medical Biochemistry Medical College Jagiellonian University Krakow Poland

Department of Biochemistry and Molecular Biology University of Granada Granada Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública Madrid 28029 Spain; GENYO Centre for Genomics and Oncological Research Genomic Oncology department Granada Spain; Instituto de Investigación Biosanitaria Ibs Granada Granada Spain

Department of Biology University of Pisa Pisa Italy

General Surgery Unit Department of Translational Research and New Technologies in Medicine and Surgery University of Pisa Italy

Institut Català d'Oncologia L'Hospitalet de Llobregat Barcelona Spain

Molecular Epidemiology of Cancer Group UCD Conway Institute School of Biomolecular and Biomedical Science University College Dublin Dublin Ireland

Pancreato Biliary Endoscopy and Endosonography Division Pancreas Translational and Clinical Research Center IRCCS Ospedale San Raffaele Milan Italy

University Clinic of Gastrohepatology University Hospital Center Mother Teresa Tirana Albania

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