Abstract 490: <i>HLA-A*02:01</i> allele is associated with decreased risk and a longer survival in pancreatic cancer: Results from an exhaustive analysis of the <i>HLA</i> variation in PDAC

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths by 2030, largely due to its asymptomatic nature at early stages, and the complex interplay of genetic and environmental risk factors. This underscores the urgent need for new biomarkers to improve PDAC prognosis. While the influence of the human leukocyte antigen (HLA) region on cancer prognosis has been studied in cancers like head and neck squamous cell carcinoma, its role in PDAC survival remains unexplored. Therefore, our main objective was to investigate the association between genetic variability within the HLA region and PDAC prognosis. Material and methods: We analyzed HLA I and II alleles within the PanGenEU study, a multicentric case-control study comprising 1317 PDAC cases and 700 controls. To validate our findings, we used external databases including the UK Biobank, TCGA, PAN-NGS trial, and Caris trial. Genotyped data was used to impute HLA alleles of eight loci (A, C, B, DRB1, DQA1, DQB1, DPA1, and DPB1) through the SNP2HLA software. The association between HLA alleles and PDAC survival was assessed using Cox proportional-hazards regression models, including the KRAS mutation profile and adjusting for potential confounders. The summary statistics from the Cox models performed in each study population were then meta-analyzed using a random-effects model with the rma.uni function of the metafor R package. Results: PDAC patients carrying the HLA-A*02:01 allele displayed improved overall survival compared to non-carriers [HR=0.87, 95%CI 0.76-0.99]. In addition, carriers of HLA-A*02:01 allele with KRASG12V mutated tumors had significantly better overall survival than non-carriers with any of the other KRAS mutations [HR=0.13, 95%CI 0.02-0.77], pointing to a host-tumor genetic interaction. We validated this interaction in early-stage PDAC tumors [HR=0.16, 95%CI 0.03-0.86]. Conclusions: This research identifies HLA-A*02:01, with a prevalence of 20% in the European population, as a key biomarker for better PDAC prognosis. Moreover, HLA-A*02:01 interacts with KRASG12V mutated tumors leading to improved survival of PDAC patients. These latter results underscore the importance of refining clinical trials to include HLA allele and KRAS mutation profiling. Importantly, our findings are crucial for stratifying PDAC patients based on their genetic background and tumor mutational profile, which can guide treatment strategies. Citation Format: Alberto Langtry, Raul Rabadan, Lola Alonso, Casper van Eijck, Teresa Macarulla, Rita T. Lawlor, Alfredo Carrato, Rafael Alvarez-Gallego, Mar Iglesias, Xavier Molero, Matthias Löhr, Christopher W. Michalski, José Perea, Michael O'Rorke, Victor M. Barberà, Adonina Tardón, Antoni Farré, Luís Muñoz-Bellvís, Tatjana Crnogorac-Jurcevic, Enrique Domínguez-Muñoz, Thomas Gress, William Greenhalf, Linda Sharp, Sergio Sabroso, Ioan Filip, Gaby Strijk, Florian Castet, Joaquim Balsells, Eithne Costello, Jörg Kleeff, Bo Kong, Josefina Mora, Damian O'Driscoll, Aldo Scarpa, Weimin Ye, Francisco X. Real, Nuria Malats, Evangelina López de Maturana. HLA-A*02:01 allele is associated with decreased risk and a longer survival in pancreatic cancer: Results from an exhaustive analysis of the HLA variation in PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 490.