{Reference Type}: Journal Article
{Title}: A comprehensive analysis of germline predisposition to early-onset ovarian cancer.
{Author}: Horackova K;Zemankova P;Nehasil P;Vocka M;Hovhannisyan M;Matejkova K;Janatova M;Cerna M;Kleiblova P;Jelinkova S;Stastna B;Just P;Dolezalova T;Nemcova B;Urbanova M;Koudova M;Hazova J;Machackova E;Foretova L;Stranecky V;Zikan M;Kleibl Z;Soukupova J;
{Journal}: Sci Rep
{Volume}: 14
{Issue}: 1
{Year}: 2024 07 13
{Factor}: 4.996
{DOI}: 10.1038/s41598-024-66324-2
{Abstract}: 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.