2026-10-11T12:38:02Z https://api.figshare.com/v2/oai

oai:figshare.com:article/32639973 2026-10-01T16:35:23Z portal_1172 item_type_8 month_year_10_2026

Functional characterisation of the 5p15.33 pancreatic cancer risk locus Aidan O'Brien (5082428) PUREID: 610111980 Pancreatic ductal adenocarcinoma GWAS CRISPR functional genomics genetic epidemiology Genome-wide association studies (GWAS) have identified common alleles at 5p15.33 associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). These associations likely involve allele-specific changes in the cis-regulation of TERT and CLPTM1L. However, the exact mechanisms remain unclear. To address this, I integrated statistical fine mapping of GWAS data with massively parallel reporter assays (MPRA) and a CRISPRi screen across PDAC cell lines. My approach identified several variants with potential allele-specific transcriptional activity. An intronic variable number tandem repeat (VNTR) in CLPTM1L  was highlighted as a strong transcriptional enhancer. Using PacBio sequencing, I genotyped VNTR alleles in European ancestry samples and imputed subsequent genotypes into a large PDAC GWAS, confirming that longer VNTRs are associated with increased risk. Dual luciferase assays indicated that Hippo pathway transcription factors mediate this enhancer activity.<br><br><i>Thesis embargoed until 31 December 2026.</i> 2026-10-01T16:35:23Z Text Thesis 10.17034/32639973.v1 https://figshare.com/articles/thesis/Functional_characterisation_of_the_5p15_33_pancreatic_cancer_risk_locus/32639973 All Rights Reserved Open Access after 2026-12-31