Functional characterisation of the 5p15.33 pancreatic cancer risk locus

Abstract

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.

Thesis embargoed until 31 December 2026.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Department of Education Northern Ireland & US National Cancer Institute
Supervisor	Nick Orr (Supervisor) & Laufey Amundadottir (Supervisor)