PDF(Pubmed)
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.
摘要：
诊断为≤30yo的卵巢癌（OC）亚群代表了一个独特的亚组，在许多方面与迟发性OC表现出差异。包括不确定的种系癌症倾向。我们用HLA分型进行DNA/RNA-WES,与组织学/分期匹配的迟发性和未选择的OC患者相比，123例早发性OC患者的PRS评估和生存分析，和人口匹配的控制。只有6/123（4.9％）的早发性OC患者在高外显率OC易感性基因中携带种系致病变异（GPV）。然而，我们对早发性OC患者的综合种系分析显示了两种不同的潜在种系易感性轨迹.首先,过度表达分析强调了与乳腺癌（BC）的联系，该联系得到了早发性OC中CHEK2GPV富集的支持（p=1.2×10-4），和推测为BC特异性的PRS313，它成功地将早发性OC患者与对照组分层（p=0.03）。第二条途径指向受损的免疫反应，LY75-CD302GPV（p=8.3×10-4）表明，与对照组相比，HLA多样性降低（p=3×10-7）。此外，我们发现,与对照组相比,早发型OC患者的GPV总体负荷显著较高(p=3.8×10-4).早发性OC的遗传易感性似乎是一个异质性和复杂的过程，超出了传统的孟德尔单基因对遗传性癌症易感性的理解，对免疫系统有重要作用。我们推测，与特定GPV相比，累积的总体GPV负担可能会增加OC风险，同时HLA多样性降低。
