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Abstract：
Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study.
Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons.
Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 × 10-4). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers.
In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.
Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons.
Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 × 10-4). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers.
In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.
摘要：
儿科癌症是儿童疾病死亡的主要原因，尽管总体生存率有所提高。种系遗传易感性对儿科癌症幸存者的贡献尚未得到广泛表征。我们在儿童癌症幸存者研究的5451名长期儿科癌症幸存者中评估了致病或可能致病（P/LP）变异的频率。
对5451例儿科癌症幸存者（诊断后存活≥5年的病例；n=5105例欧洲）和597例欧洲无癌成年人（对照）的种系DNA进行了外显子组测序。分析的重点是比较237个癌症易感基因和60个常染色体显性高到中度外显基因的子集中罕见P/LP变异的频率。用于病例-病例和病例对照比较。
■在欧洲案例中，4.1％的人在高至中外显率常染色体显性基因中具有P/LP变异，而对照组为1.3％（双侧P=3×10-4）。P/LP变异的频率最高的是通常与成人发病相关的基因，而不是儿科癌症。包括BRCA1/2,FH,PALB2、PMS2和CDKN2A。P/LP变体的统计学显著过量，在对多个测试进行校正后，在中枢神经系统癌症患者中检测到(NF1，SUFU，TSC1,PTCH2),Wilms肿瘤（WT1，REST），非霍奇金淋巴瘤（PMS2），和软组织肉瘤（SDHB，DICER1，TP53，ERCC4，FGFR3）与其他儿科癌症相比。
■在长期儿科癌症幸存者中，我们在癌症易感基因中发现了P/LP变异,这些变异以前与儿科癌症无关,并证实了已知的相关性.进一步表征儿科癌症中这些基因的变异对于为患者及其家人提供最佳遗传咨询将是重要的。
对5451例儿科癌症幸存者（诊断后存活≥5年的病例；n=5105例欧洲）和597例欧洲无癌成年人（对照）的种系DNA进行了外显子组测序。分析的重点是比较237个癌症易感基因和60个常染色体显性高到中度外显基因的子集中罕见P/LP变异的频率。用于病例-病例和病例对照比较。
■在欧洲案例中，4.1％的人在高至中外显率常染色体显性基因中具有P/LP变异，而对照组为1.3％（双侧P=3×10-4）。P/LP变异的频率最高的是通常与成人发病相关的基因，而不是儿科癌症。包括BRCA1/2,FH,PALB2、PMS2和CDKN2A。P/LP变体的统计学显著过量，在对多个测试进行校正后，在中枢神经系统癌症患者中检测到(NF1，SUFU，TSC1,PTCH2),Wilms肿瘤（WT1，REST），非霍奇金淋巴瘤（PMS2），和软组织肉瘤（SDHB，DICER1，TP53，ERCC4，FGFR3）与其他儿科癌症相比。
■在长期儿科癌症幸存者中，我们在癌症易感基因中发现了P/LP变异,这些变异以前与儿科癌症无关,并证实了已知的相关性.进一步表征儿科癌症中这些基因的变异对于为患者及其家人提供最佳遗传咨询将是重要的。
