Abstract 1475: Uncovering the functional variants and target genes of the 7q32 pancreatic cancer risk locus

Abstract In western nations, pancreatic ductal adenocarcinoma (PDAC) is set to become second leading cause of cancer mortality over the next decade. Despite advances in treatment, PDAC has a 5-year survival rate of only ~9%, necessitating a better understanding of its etiology. Risk factors for PDAC are both environmental and genetic, with heritability estimated at around 20%. However, highly penetrant coding variants are rare within the population and have been estimated to account for as little as 1% of the phenotypic variance for PDAC. In an effort to identify common PDAC susceptibility alleles, genome-wide association studies (GWAS) have identified 17 loci at which germline variants associate with PDAC risk. Mostly localizing to non-coding loci, many such risk variants are expected to confer risk via allele-specific changes in transcription factor binding, leading to altered target gene expression over a lifetime. The identification of functional variants from GWAS is complicated by the correlation of alleles through linkage disequilibrium (LD). Here, we have leveraged Bayesian fine mapping to identify a credible set of seven single nucleotide polymorphisms (SNPs) in high LD at the 7q32 risk locus. Fine-mapped variants were annotated using epigenomic datasets we previously generated from a range of pancreatic cell lines, organoids and primary patient samples, encompassing histone modification marks (ChIP-seq), open chromatin (ATAC-seq) and chromatin conformation capture (Capture-HiC, HiChIP). Two variants from the credible set (rs6971499 and rs6970779) were found to consistently lie within regions annotated as super-enhancers and marked by open chromatin within our data. Both SNPs exhibit chromatin looping to the promoters of nearby plausible target genes LINC-PINT and miR29a. Electrophoretic mobility shift assays (EMSA) illustrate that rs6971499-T and rs6970779-G exhibit allele-specific protein binding in PANC-1 and MIA PaCa-2 cell lines, while luciferase reporter assays in the same cell lines demonstrate that both alleles drive significant changes in transcriptional activity. Ongoing proteomic experiments aim to identify the transcription factors differentially bound to these alleles, while CRISPR methods are being employed to validate enhancer variants in their native chromatin context. Future experiments may further characterise these transcription factors and their target genes with an eye toward better understanding their roles in PDAC carcinogenesis. Citation Format: Aidan O'Brien, Jason W. Hoskins, Daina R. Eiser, Katelyn E. Connelly, Jun Zhong, Thorkell Andresson, Irene Collins, Pancreatic Cancer Cohort Consortium, Pancreatic Cancer Case-Control Consortium, Stephen J. Chanock, Alison P. Klein, H. Efsun Arda, Laufey T. Amundadottir. Uncovering the functional variants and target genes of the 7q32 pancreatic cancer risk locus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1475.