Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Department of Digital Health, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, South Korea.
Nat Commun. 2024 Sep 27;15(1):8360. doi: 10.1038/s41467-024-52128-5.
Germline genetic context may play a significant role in the development and evolution of cancer, particularly in childhood cancers such as neuroblastoma. This study investigates the role of putatively functional germline variants in neuroblastoma, even if they do not directly increase disease risk. Our whole-exome sequencing analysis of 125 patients with neuroblastoma reveals a positive correlation between germline variant burden and somatic mutations. Moreover, patients with higher germline variant burden exhibit worse outcomes. Similar findings are observed in the independent neuroblastoma cohort where a higher germline variant burden correlates with a higher somatic mutational burden and a worse overall survival outcome. However, contrasting results emerge in adult-onset cancer, emphasizing the importance of germline genetics in neuroblastoma. The enrichment of putatively functional germline variants in cancer predisposition genes is borderline significant when compared to healthy populations (P = 0.077; Odds Ratio, 1.45; 95% confidence intervals, 0.94-2.21) and significantly more pronounced against adult-onset cancers (P = 0.016; Odds Ratio, 2.13; 95% confidence intervals, 1.10-3.91). Additionally, the presence of these variants proves to have prognostic significance in neuroblastoma (log-rank P < 0.001), and combining germline with clinical risk factors notably improves survival predictions.
胚系遗传背景可能在癌症的发生和发展中起重要作用，尤其是在儿童癌症如神经母细胞瘤中。本研究探讨了假定的功能性胚系变异在神经母细胞瘤中的作用，即使它们不会直接增加疾病风险。我们对 125 例神经母细胞瘤患者的全外显子组测序分析显示，胚系变异负担与体细胞突变之间存在正相关。此外，胚系变异负担较高的患者预后较差。在独立的神经母细胞瘤队列中也观察到了类似的发现，其中较高的胚系变异负担与较高的体细胞突变负担和较差的总生存结局相关。然而，在成人发病的癌症中出现了相反的结果，强调了胚系遗传学在神经母细胞瘤中的重要性。与健康人群相比，癌症易感性基因中假定的功能性胚系变异的富集具有边缘显著意义（P=0.077；优势比，1.45；95%置信区间，0.94-2.21），与成人发病的癌症相比更为显著（P=0.016；优势比，2.13；95%置信区间，1.10-3.91）。此外，这些变异的存在在神经母细胞瘤中具有预后意义（对数秩 P<0.001），并且将胚系与临床危险因素相结合可显著改善生存预测。
