Abstract A101: Genome-wide association study in Taiwanese Han uncovers OR1A1 as a metastasis suppressor in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality due to late-stage diagnosis and limited therapeutic targets. Most genome-wide association studies (GWAS) have focused on European populations, leaving the genetic landscape of PDAC in Asian populations under-characterized. This study aimed to identify population-specific susceptibility loci in the Taiwan-Han population. Through a GWAS in a Taiwan-Chinese cohort and validated findings through a transethnic meta-analysis, OR1A1 is identified as a risk gene associated with PDAC risk. Transethnic meta-analysis confirmed OR1A1 as a shared candidate gene. Risk SNPs promote regional DNA hypermethylation and repressive histone modifications at the OR1A1 promoter. PDAC cells showed significantly higher methylation and lower OR1A1 expression compared to non-cancer cells; this was partially reversed by demethylating agents. In a syngeneic mouse model, Or1a1 depletion significantly increased liver metastatic burden without affecting primary tumor growth, identifying OR1A1 as a metastasis suppressor. Clinical observation from public databases revealed OR1A1 downregulation in 80% of patients, correlating with lymph node metastasis and poorer disease-free survival. This study identifies OR1A1 as a novel germline susceptibility locus and a functional metastasis suppressor in PDAC.