%0 Journal Article
%T A comprehensive analysis of germline predisposition to early-onset ovarian cancer.
%A Horackova K
%A Zemankova P
%A Nehasil P
%A Vocka M
%A Hovhannisyan M
%A Matejkova K
%A Janatova M
%A Cerna M
%A Kleiblova P
%A Jelinkova S
%A Stastna B
%A Just P
%A Dolezalova T
%A Nemcova B
%A Urbanova M
%A Koudova M
%A Hazova J
%A Machackova E
%A Foretova L
%A Stranecky V
%A Zikan M
%A Kleibl Z
%A Soukupova J
%J Sci Rep
%V 14
%N 1
%D 2024 07 13
%M 39003285
%F 4.996
%R 10.1038/s41598-024-66324-2
%X The subset of ovarian cancer (OC) diagnosed ≤ 30yo represents a distinct subgroup exhibiting disparities from late-onset OC in many aspects, including indefinite germline cancer predisposition. We performed DNA/RNA-WES with HLA-typing, PRS assessment and survival analysis in 123 early-onset OC-patients compared to histology/stage-matched late-onset and unselected OC-patients, and population-matched controls. Only 6/123(4.9%) early-onset OC-patients carried a germline pathogenic variant (GPV) in high-penetrance OC-predisposition genes. Nevertheless, our comprehensive germline analysis of early-onset OC-patients revealed two divergent trajectories of potential germline susceptibility. Firstly, overrepresentation analysis highlighted a connection to breast cancer (BC) that was supported by the CHEK2 GPV enrichment in early-onset OC(p = 1.2 × 10-4), and the presumably BC-specific PRS313, which successfully stratified early-onset OC-patients from controls(p = 0.03). The second avenue pointed towards the impaired immune response, indicated by LY75-CD302 GPV(p = 8.3 × 10-4) and diminished HLA diversity compared with controls(p = 3 × 10-7). Furthermore, we found a significantly higher overall GPV burden in early-onset OC-patients compared to controls(p = 3.8 × 10-4). The genetic predisposition to early-onset OC appears to be a heterogeneous and complex process that goes beyond the traditional Mendelian monogenic understanding of hereditary cancer predisposition, with a significant role of the immune system. We speculate that rather a cumulative overall GPV burden than specific GPV may potentially increase OC risk, concomitantly with reduced HLA diversity.