Mapping Genetic Regulation of Transcription to Identify Functional Variants and Genes Associated with Pancreatic...

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Pancreatic cancer is a highly lethal malignancy with complex genetic underpinnings.
• Genome-wide association studies (GWAS) have identified numerous risk loci, but linking noncoding variants to specific genes remains challenging.

Purpose of the Study:

• To construct a genome-wide regulatory map for pancreatic cancer.
• To integrate expression quantitative trait loci (eQTL) data with GWAS to identify and prioritize causal variants associated with pancreatic cancer risk.
• To functionally characterize a novel risk-modulating genetic variant.

Main Methods:

• Expression quantitative trait loci (eQTL) analysis on 482 pancreatic tissues.
• Meta-analysis of genome-wide association studies (GWAS).
• Functional assays including ZNF263 binding, chromatin interaction analysis, and gene expression studies.

Main Results:

• Identified 82 significant variants and 15 target genes associated with pancreatic cancer risk.
• Validated rs11102484 in an independent cohort, showing the G allele significantly reduces pancreatic cancer risk (OR=0.85).
• Demonstrated that the protective G allele of rs11102484 impairs ZNF263 binding, leading to increased ST7L expression, which suppresses cancer cell proliferation via AKT/β-catenin signaling.

Conclusions:

• Implicated functional genes in pancreatic cancer susceptibility.
• Characterized a regulatory variant (rs11102484) that modulates ST7L expression, providing a mechanism for GWAS findings.
• Advanced the understanding of pancreatic cancer biology and identified a potential therapeutic target through ST7L modulation.