Treger Taryn D, Wegert Jenny, Wenger Anna, Coorens Tim H H, Al-Saadi Reem, Kemps Paul G, Kennedy Jonathan, Parks Conor, Anderson Nathaniel D, Hodder Angus, Letunovska Aleksandra, Jung Hyunchul, Ogbonnah Toochi, Trinh Mi K, Lee-Six Henry, Morcrette Guillaume, van den Heuvel-Eibrink Marry M, Drost Jarno, van Boxtel Ruben, Bertrums Eline J M, Goemans Bianca F, Antoniou Evangelia, Reinhardt Dirk, Streitenberger Heike, Ziegler Barbara, Bartram Jack, Hutchinson John C, Vujanic Gordan M, Vokuhl Christian, Chowdhury Tanzina, Furtwängler Rhoikos, Graf Norbert, Pritchard-Jones Kathy, Gessler Manfred, Behjati Sam
Wellcome Sanger Institute, Hinxton, United Kingdom.
Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom.
Cancer Discov. 2025 Feb 7;15(2):286-298. doi: 10.1158/2159-8290.CD-24-0878.
Approximately 10% of children with cancer harbor a mutation in a predisposition gene. In children with the kidney cancer Wilms tumor, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumorigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumor, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukemias), utilizing whole-genome sequencing, RNA sequencing, and genome-wide methylation, validating our findings in an independent cohort. Tumor development differed in children harboring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high-risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumorigenesis, suggesting a variant-specific approach to managing children merits consideration. Significance: Tumors that arise in children with a cancer predisposition may develop through the same mutational pathways as sporadic tumors. We examined this question in the childhood kidney cancer, Wilms tumor. We found that certain predispositions dictate the genetic development of tumors, with clinical implications for these children. See related commentary by Brzezinski and Malkin, p. 258.
约10%的癌症患儿携带易感基因的突变。在患肾癌（威尔姆斯瘤）的儿童中，这一比例高达30%。某些易感性与特定的组织学和临床特征相关，提示肿瘤发生存在差异。为对此进行研究，我们组建了一个由137名威尔姆斯瘤患儿组成的队列，其中71名携带致病种系或嵌合变异。我们利用全基因组测序、RNA测序和全基因组甲基化检测了237个肿瘤（包括两例继发性白血病），并在一个独立队列中验证了我们的发现。携带易感性的儿童肿瘤发生情况有所不同，这取决于变异基因及其发育时间。差异贯穿于驱动事件的全部过程，包括高风险突变、正常肾脏的克隆结构以及同一个体肿瘤之间的相关性。我们的研究结果表明，易感性可能预先决定了威尔姆斯瘤的发生，这表明针对儿童管理的变异特异性方法值得考虑。意义：有癌症易感性的儿童所患肿瘤可能通过与散发性肿瘤相同的突变途径发展而来。我们在儿童肾癌威尔姆斯瘤中研究了这个问题。我们发现某些易感性决定了肿瘤的基因发展，对这些儿童具有临床意义。见Brzezinski和Malkin的相关评论，第258页。
