title: Identification of Novel Germline Genetic Variants Associated with Pancreatic Cancer Risk by Using Genome-Wide Studies
creator: Ünal, Pelin
subject: ddc-500
subject: 500 Natural sciences and mathematics
subject: ddc-570
subject: 570 Life sciences
description: Pancreatic cancer, whose most common form is pancreatic ductal adenocarcinoma (PDAC), is one of the most aggressive and fatal cancers, with minimal progress in early detection and treatment. While genome-wide association studies (GWAS) have identified several common germline variants, a large proportion of PDAC heritability remains unexplained. In this thesis project, I applied post-GWAS and secondary analysis strategies to uncover novel genetic risk factors, specifically focusing on regulatory regions, rare variants, and genes involved in cognition network.  In the first part of the study, I explored polymorphisms in transcription factor binding sites (TFBS) and enhancers. Through meta-analyses across independent cohorts, I identified rs2472632 near CCDC34 as a candidate regulatory variant, supported by enhancer signals and transcription factor motif overlap. This finding highlights a potential mechanism of PDAC risk originating from non-coding genomic elements. The second part of the project focused on genome-wide rare variant association analyses. Using both annotation-weighted and unweighted gene-based tests, I discovered significant associations in several genes, including RIPK2, PTPRT, CLU, and PARD3, that are functionally linked to cell signaling, immune regulation, and epithelial structure. These genes provide promising leads for understanding the role of rare germline variation in PDAC. Finally, I investigated a novel hypothesis connecting cognition-related genes to PDAC risk. I identified significant associations in genes such as RP11-255M2.3, LGR4, RORA and LINC00907 across two large datasets. This supports the intriguing possibility that neurogenetic factors may contribute to cancer susceptibility through stress response or neuroendocrine regulation.  By combining large-scale datasets with advanced post-GWAS methods, this thesis reveals overlooked layers of genetic risk in PDAC. Despite challenges such as dataset heterogeneity and replication of rare variants, the findings offer new perspectives and lay the groundwork for future functional and translational studies in cancer genomics.
date: 2025
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserver/37416/1/Pelin_Unal_doctorate_thesis_final.pdf
identifier: DOI:10.11588/heidok.00037416
identifier: urn:nbn:de:bsz:16-heidok-374161
identifier:   Ünal, Pelin  (2025) Identification of Novel Germline Genetic Variants Associated with Pancreatic Cancer Risk by Using Genome-Wide Studies.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/37416/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng