P04.01 Reduced HLA diversity and impaired immune surveillance in very early-onset ovarian cancer patients

Background Reduced diversity at human leukocyte antigen (HLA) loci may compromise immune recognition of tumor neoantigens. We hypothesized that decreased heterozygosity at HLA loci is associated with an increased risk of developing very early onset ovarian cancer (OC). Unlike late-onset OC, OC diagnosed before 30 years of age is rarely attributable to germline pathogenic variants (GPV) in established high-to-moderate-penetrance OC predisposition genes, suggesting alternative mechanisms of genetic susceptibility, including immune-related factors.Methods We performed a comprehensive germline analysis of 123 early-onset OC patients using DNA and RNA whole-exome sequencing, complemented by HLA genotyping and polygenic risk score analyses. Genetic findings were evaluated in clinical and histopathological context and compared with multiple control cohorts, including 378 population-matched controls, 227 non-cancer female controls, and 5099 unselected individuals from Czech National Marrow Donors Registry.Results HLA analysis revealed a significantly increased frequency of HLA homozygosity in early-onset OC patients compared with controls, affecting both class I and class II loci. We also observed a significant enrichment of specific class I (HLA-A*36:01, HLA-B*53:01) and II (HLA-DRB1*11:01, HLA-DQA1*01:03) alleles. Gene burden analysis further identified enrichment of GPV in immune-related genes, notably LY75-CD302, which encode receptors involved in antigen uptake and HLA class I–mediated antigen presentation.Conclusions Early-onset OC is characterized by a distinct and highly heterogeneous germline genetic architecture. Our findings implicate impaired immune surveillance—reflected by reduced HLA diversity and enrichment of immune-related GPV—as a potential contributor to disease susceptibility.Supported by the Ministry of Health of the Czech Republic: DRO-VFN-00064165; Charles University: COOPERATIO, UNCE/24/MED/022; and the Ministry of Education Youth and Sports of the Czech Republic: MULTIOMICS_CZ (Programme Johannes Amos Comenius, ID Project CZ.02.01.01/00/23_020/0008540) – Co-funded by the European Union.