诊断为 ≤≤30 岁的卵巢癌 (OC) 亚组代表了一个独特的亚组，在许多方面与晚发 OC 存在差异，包括不确定的种系癌症易感性。我们对 123 名早发 OC 患者进行了 DNA/RNA-WES 与 HLA 分型、PRS 评估和生存分析，并与组织学/分期匹配的晚发和未选择的 OC 患者以及人群匹配的对照进行比较。只有 6/123（4.9%）的早发 OC 患者在高外显率 OC 易感基因中携带种系致病性变异（GPV）。尽管如此，我们对早发 OC 患者的全面种系分析揭示了潜在种系易感性的两种不同轨迹。首先，过度代表性分析强调了与乳腺癌（BC）的联系，这一点得到了早发性 OC 中 CHEK2 GPV 富集的支持（p = 1.2 × 10-4），以及可能是 BC 特异性的 PRS313，该 PRS313 成功地对早发性乳腺癌进行了分层OC-对照患者（p = 0.03）。第二条途径指向免疫反应受损，由 LY75-CD302 GPV 表明（p = 8.3 × 10-4），与对照相比，HLA 多样性减少（p = 3 × 10-7）。此外，我们发现，与对照组相比，早发性 OC 患者的总体 GPV 负担显着更高（p = 3.8 × 10-4）。早发性卵巢癌的遗传倾向似乎是一个异质且复杂的过程，超出了传统孟德尔单基因对遗传性癌症倾向的理解，其中免疫系统发挥着重要作用。我们推测累积的总体 GPV 负担而不是特定的 GPV 可能会增加 OC 风险，同时伴随着 HLA 多样性的减少。© 2024。作者。

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.© 2024. The Author(s).