Germline functional variants contribute to somatic mutation and outcomes in neuroblastoma

Eun Seop Seo, Ji Won Lee, Jinyeong Lim, Sunghwan Shin, Hee Won Cho, Hee Young Ju, Keon Hee Yoo, Ki Woong Sung () and Woong-Yang Park ()
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Eun Seop Seo: Sungkyunkwan University School of Medicine
Ji Won Lee: Sungkyunkwan University School of Medicine
Jinyeong Lim: Samsung Medical Center
Sunghwan Shin: Inje University Ilsan Paik Hospital
Hee Won Cho: Sungkyunkwan University School of Medicine
Hee Young Ju: Sungkyunkwan University School of Medicine
Keon Hee Yoo: Sungkyunkwan University School of Medicine
Ki Woong Sung: Sungkyunkwan University School of Medicine
Woong-Yang Park: Sungkyunkwan University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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

Date: 2024
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DOI: 10.1038/s41467-024-52128-5

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