Dataset Information

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

ABSTRACT: Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10^-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10^-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10^-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10^-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

SUBMITTER: Unal P

PROVIDER: S-EPMC10837899 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Ünal Pelin P Lu Ye Y Bueno-de-Mesquita Bas B van Eijck Casper H J CHJ Talar-Wojnarowska Renata R Szentesi Andrea A Gazouli Maria M Kreivenaite Edita E Tavano Francesca F Małecka-Wojciesko Ewa E Erőss Bálint B Oliverius Martin M Bunduc Stefania S Nóbrega Aoki Mateus M Vodickova Ludmila L Boggi Ugo U Giaccherini Matteo M Kondrackiene Jurate J Chammas Roger R Palmieri Orazio O Theodoropoulos George E GE Bijlsma Maarten F MF Basso Daniela D Mohelnikova-Duchonova Beatrice B Soucek Pavel P Izbicki Jakob R JR Kiudelis Vytautas V Vanella Giuseppe G Arcidiacono Paolo Giorgio PG Włodarczyk Barbara B Hackert Thilo T Schöttker Ben B Uzunoglu Faik G FG Bambi Franco F Goetz Mara M Hlavac Viktor V Brenner Hermann H Perri Francesco F Carrara Silvia S Landi Stefano S Hegyi Péter P Dijk Frederike F Maiello Evaristo E Capretti Giovanni G Testoni Sabrina Gloria Giulia SGG Petrone Maria Chiara MC Stocker Hannah H Ermini Stefano S Archibugi Livia L Gentiluomo Manuel M Cavestro Giulia Martina GM Pezzilli Raffaele R Di Franco Gregorio G Milanetto Anna Caterina AC Sperti Cosimo C Neoptolemos John P JP Morelli Luca L Vokacova Klara K Pasquali Claudio C Lawlor Rita T RT Bazzocchi Francesca F Kupcinskas Juozas J Capurso Gabriele G Campa Daniele D Canzian Federico F

Human genomics 20240202 1

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regul ...[more]

PMID: 38308339

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Project description:BackgroundWe have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites.MethodsFor this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain.ResultsThe updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition.ConclusionsThe updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/ ) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid.

Dataset Information

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Publications

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

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