Early-onset ovarian cancer: a comprehensive analysis

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 whole exome sequencing together with human leukocyte antigen(HLA) typing, polygenic risk score(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, including a single carrier of GPV in BRCA1 and BRCA2 each. 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 enrichment of GPV in CHEK2 in early-onset OC( p = 1.2×10 − 4 ), and the presumably BC-specific PRS 313 , which successfully stratified early-onset OC from controls( p = 0.03). The second avenue pointed towards the impaired immune response, indicated by GPV in LY75-CD302 ( p = 8.3×10 − 4 ) and coupled with diminished HLA diversity compared with controls( p = 3×10 − 7 ). Furthermore, we found a significantly higher GPV burden in early-onset OC patients compared to controls( p = 3.8×10 − 4 ). We observed survival advantage in early-onset OC patients compared with both age-unselected and histology/stage-matched late-onset OC patients lacking gBRCA1/2 . 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 GPV burden than specific GPV may potentially increase OC risk, concomitantly with reduced HLA diversity.