HLA-A*02:01allele is associated with decreased risk and a longer survival in pancreatic cancer: Results from an exhaustive analysis of theHLAvariation in PDAC

ABSTRACT Genetic susceptibility loci are associated with PDAC risk and survival, but the impact of germline HLA region variation remains largely unexplored. This study examined HLA I-II alleles within the PanGenEU study and validated our findings using external datasets (UK Biobank, TCGA, PAN-NGS trial, and Caris trial). HLA-A*02:01and HLA-B*49 alleles were linked to a decreased risk of PDAC, whereas HLA-B*39 , HLA-DPB1*04, and HLA-A*26:01 were directly associated with increased risk. PDAC patients carrying the HLA-A*02:01 allele also showed lower mortality rates, with the effect being more pronounced in those with KRAS G12V mutations, pointing to a host*tumor genetic interaction. This research highlights HLA-A*02:01 , found in 20% of Europeans, as a marker for reduced PDAC risk and mortality, especially in KRAS G12V mutated tumors. Results from this study could enhance personalized medicine for PDAC by identifying patients who may benefit from regular screenings through tailored risk assessments. Importantly, our findings are crucial for stratifying PDAC patients based on their genetic background and tumor mutational profile, which can guide treatment strategies.