Maoxiang Qian, Xueyuan Cao, Wenjian Yang, Cheng Cheng, Hui Zhang, Takaya Moriyama, Gerard Zambetti, Kim E. Nichols, Ching-Hon Pui, Charles G. Mullighan, William E. Evans, Mary V. Relling, and Jun J. Yang, St Jude Children's Research Hospital, Memphis, TN; Meenakshi Devidas and Yunfeng Dai, University of Florida, Gainesville, FL; Andrew Carroll, University of Alabama at Birmingham, Birmingham, AL; Nyla A. Heerema and Julie M. Gastier-Foster, The Ohio State University and Wexner Medical Center; Julie M. Gastier-Foster and Elaine R. Mardis, Nationwide Children's Hospital, Columbus, OH; Hui Zhang, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong; Heng Xu, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China; Elizabeth Raetz, University of Utah, Salt Lake City, UT; Eric Larsen, Maine Children's Cancer Program, Scarborough, ME; Naomi Winick, University of Texas Southwestern Medical Center, Dallas; W. Paul Bowman, Cook Children's Medical Center, Fort Worth, TX; Paul L. Martin, Duke University, Durham, NC; Robert Fulton, Washington University School of Medicine, St Louis, MO; Michael Borowitz, Johns Hopkins Medical Institute, Baltimore, MD; Brent Wood, University of Washington, Seattle, WA; William L. Carroll, New York University, New York, NY; Stephen P. Hunger, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA; and Mignon L. Loh, Benioff Children's Hospital and University of California, San Francisco, San Francisco, CA.
J Clin Oncol. 2018 Feb 20;36(6):591-599. doi: 10.1200/JCO.2017.75.5215. Epub 2018 Jan 4.
Purpose Germline TP53 variation is the genetic basis of Li-Fraumeni syndrome, a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in childhood hypodiploid acute lymphoblastic leukemia (ALL) suggest that this type of leukemia is another manifestation of Li-Fraumeni syndrome; however, the pattern, prevalence, and clinical relevance of TP53 variants in childhood ALL remain unknown. Patients and Methods Targeted sequencing of TP53 coding regions was performed in 3,801 children from the Children's Oncology Group frontline ALL clinical trials, AALL0232 and P9900. TP53 variant pathogenicity was evaluated according to experimentally determined transcriptional activity, in silico prediction of damaging effects, and prevalence in non-ALL control populations. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes. Results We identified 49 unique nonsilent rare TP53 coding variants in 77 (2.0%) of 3,801 patients sequenced, of which 22 variants were classified as pathogenic. TP53 pathogenic variants were significantly over-represented in ALL compared with non-ALL controls (odds ratio, 5.2; P < .001). Children with TP53 pathogenic variants were significantly older at ALL diagnosis (median age, 15.5 years v 7.3 years; P < .001) and were more likely to have hypodiploid ALL (65.4% v 1.2%; P < .001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival and overall survival (hazard ratio, 4.2 and 3.9; P < .001 and .001, respectively). In particular, children with TP53 pathogenic variants were at a dramatically higher risk of second cancers than those without pathogenic variants, with 5-year cumulative incidence of 25.1% and 0.7% ( P < .001), respectively. Conclusion Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.
目的
胚系 TP53 变异是 Li-Fraumeni 综合征（一种具有高度外显率的癌症易感性疾病）的遗传基础。最近有报道称，胚系 TP53 变异与儿童低倍体急性淋巴细胞白血病（ALL）有关，这提示该类型白血病是 Li-Fraumeni 综合征的另一种表现形式；然而，儿童 ALL 中 TP53 变异的模式、流行率和临床相关性仍不清楚。
患者和方法
在儿童肿瘤学组一线 ALL 临床试验 AALL0232 和 P9900 中，对 3801 例患儿进行了 TP53 编码区的靶向测序。根据实验确定的转录活性、对有害影响的计算预测以及非 ALL 对照人群中的流行率，评估 TP53 变异的致病性。分析 TP53 变异与 ALL 表现特征和治疗结局的相关性。
结果
在 3801 例测序患者中，我们发现了 77 例（2.0%）患者存在 49 个独特的非同义罕见 TP53 编码变异，其中 22 个变异被归类为致病性。与非 ALL 对照相比，TP53 致病性变异在 ALL 中明显过度表达（比值比，5.2；P <.001）。携带胚系 TP53 致病性变异的患儿 ALL 诊断时年龄明显较大（中位数年龄，15.5 岁比 7.3 岁；P <.001），并且更有可能患有低倍体 ALL（65.4%比 1.2%；P <.001）。携带种系 TP53 致病性变异与不良无事件生存和总生存相关（风险比，4.2 和 3.9；P <.001 和.001）。特别是，携带 TP53 致病性变异的患儿发生第二恶性肿瘤的风险明显高于无致病性变异的患儿，5 年累积发生率分别为 25.1%和 0.7%（P <.001）。
结论
失活的胚系 TP53 变异使儿童易患 ALL，并使 ALL 治疗的结局不良，特别是发生第二恶性肿瘤的风险。
