Germline Mutations in Predisposition Genes in Pediatric Cancer.
Germline Mutations in Predisposition Genes in Pediatric Cancer.
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DOI：
10.1056/nejmoa1508054
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发表时间：
2015-12-10
期刊：
影响因子：
--
通讯作者：
Downing JR
中科院分区：
文献类型：
--
作者：
Zhang J;Walsh MF;Wu G;Edmonson MN;Gruber TA;Easton J;Hedges D;Ma X;Zhou X;Yergeau DA;Wilkinson MR;Vadodaria B;Chen X;McGee RB;Hines-Dowell S;Nuccio R;Quinn E;Shurtleff SA;Rusch M;Patel A;Becksfort JB;Wang S;Weaver MS;Ding L;Mardis ER;Wilson RK;Gajjar A;Ellison DW;Pappo AS;Pui CH;Nichols KE;Downing JR
儿童和青少年癌症易感突变的患病率和谱在很大程度上是未知的。这种突变的知识可以提高对肿瘤发生的理解，指导患者护理，并使患者和家属的遗传咨询成为可能。在1120名年龄小于20岁的患者中，我们对595名患者的全基因组、456名患者的全外显子组或69名患者的全外显子组进行了测序。我们分析了565个基因的DNA序列，其中包括60个与常染色体显性癌症易感性综合征相关的基因，以寻找种系突变的存在。突变的致病性是由一个医学专家小组通过使用癌症特异性和基因座特异性基因数据库、医学文献、计算预测和肿瘤基因组中确定的第二点来确定的。同样的方法被用于分析来自1000基因组计划中966名不知道癌症的人的数据，类似的方法被用于分析来自自闭症研究的数据（来自515名自闭症患者和208名非自闭症患者）。95名癌症患者（8.5%）发现了被认为是致病的或可能致病的突变，相比之下，1000个基因组计划中的这一比例为1.1%，自闭症研究中的这一比例为0.6%。受影响患者中最常见的突变基因是TP53（50例）、APC（6例）、BRCA2（6例）、NF1（4例）、PMS2（4例）、RB1（3例）和RUNX1（3例）。另外共有18名患者在肿瘤抑制基因中存在蛋白质截断突变。在58例易感突变和现有家族史信息的患者中，23例（40%）有癌症家族史。在患有癌症的儿童和青少年中发现了8.5%的癌症易感基因的种系突变。家族史不能预测大多数患者是否存在潜在的易感综合征。（由美国黎巴嫩叙利亚联合慈善机构和国家癌症研究所资助。）
The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism). Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer. Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.)
影响因子：
8.8
作者：
Staff S;Isola JJ;Johannsson O;Borg A;Tanner MM
通讯作者：
Tanner MM