Wang Xuexia, Sun Can-Lan, Hageman Lindsey, Smith Kandice, Singh Purnima, Desai Sunil, Hawkins Douglas S, Hudson Melissa M, Mascarenhas Leo, Neglia Joseph P, Oeffinger Kevin C, Ritchey A Kim, Robison Leslie L, Villaluna Doojduen, Landier Wendy, Bhatia Smita
Xuexia Wang, University of North Texas, Denton, TX; Can-Lan Sun, City of Hope, Duarte; Leo Mascarenhas, Children's Hospital Los Angeles, University of Southern California, Los Angeles; Doojduen Villaluna, Children's Oncology Group, Monrovia, CA; Lindsey Hageman, Kandice Smith, Purnima Singh, Wendy Landier, and Smita Bhatia, University of Alabama at Birmingham, Birmingham, AL; Sunil Desai, University of Alberta, Edmonton, Alberta, Canada; Douglas S. Hawkins, Seattle Children's Hospital, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA; Melissa M. Hudson and Leslie L. Robison, St Jude Children's Research Hospital, Memphis, TN; Joseph P. Neglia, University of Minnesota Medical School, Minneapolis, MN; Kevin C. Oeffinger, Duke University Medical Center, Durham, NC; and A. Kim Ritchey, University of Pittsburgh School of Medicine, Pittsburgh, PA.
J Clin Oncol. 2017 Nov 10;35(32):3688-3696. doi: 10.1200/JCO.2017.74.7444. Epub 2017 Oct 4.
Purpose Survivors of childhood cancer treated with cranial radiation therapy are at risk for subsequent CNS tumors. However, significant interindividual variability in risk suggests a role for genetic susceptibility and provides an opportunity to identify survivors of childhood cancer at increased risk for these tumors. Methods We curated candidate genetic variants from previously published studies in adult-onset primary CNS tumors and replicated these in survivors of childhood cancer with and without subsequent CNS tumors (82 participants and 228 matched controls). We developed prediction models to identify survivors at high or low risk for subsequent CNS tumors and validated these models in an independent matched case-control sample (25 participants and 54 controls). Results We demonstrated an association between six previously published single nucleotide polymorphisms (rs15869 [ BRCA2], rs1805389 [ LIG4], rs8079544 [ TP53], rs25489 [ XRCC1], rs1673041 [ POLD1], and rs11615 [ ERCC1]) and subsequent CNS tumors in survivors of childhood cancer. Including genetic variants in a Final Model containing age at primary cancer, sex, and cranial radiation therapy dose yielded an area under the curve of 0.81 (95% CI, 0.76 to 0.86), which was superior ( P = .002) to the Clinical Model (area under the curve, 0.73; 95% CI, 0.66 to 0.80). The prediction model was successfully validated. The sensitivity and specificity of predicting survivors of childhood cancer at highest or lowest risk of subsequent CNS tumors was 87.5% and 83.5%, respectively. Conclusion It is possible to identify survivors of childhood cancer at high or low risk for subsequent CNS tumors on the basis of genetic and clinical information. This information can be used to inform surveillance for early detection of subsequent CNS tumors.
目的 接受颅脑放射治疗的儿童癌症幸存者有发生后续中枢神经系统肿瘤的风险。然而，风险存在显著的个体差异，提示遗传易感性起作用，并为识别这些肿瘤风险增加的儿童癌症幸存者提供了机会。方法 我们从先前发表的成人原发性中枢神经系统肿瘤研究中挑选候选基因变异，并在有或没有后续中枢神经系统肿瘤的儿童癌症幸存者（82名参与者和228名匹配对照）中进行复制。我们开发了预测模型，以识别后续中枢神经系统肿瘤风险高或低的幸存者，并在独立的匹配病例对照样本（25名参与者和54名对照）中验证这些模型。结果 我们证明了六个先前发表的单核苷酸多态性（rs15869 [BRCA2]、rs1805389 [LIG4]、rs8079544 [TP53]、rs25489 [XRCC1]、rs1673041 [POLD1] 和 rs11615 [ERCC1]）与儿童癌症幸存者后续中枢神经系统肿瘤之间存在关联。在包含原发癌症年龄、性别和颅脑放射治疗剂量的最终模型中纳入基因变异，得到的曲线下面积为0.81（95%CI，0.76至0.86），优于临床模型（曲线下面积，0.73；95%CI，0.66至0.80）（P = 0.002）。预测模型得到成功验证。预测后续中枢神经系统肿瘤风险最高或最低的儿童癌症幸存者的敏感性和特异性分别为87.5%和83.5%。结论 基于遗传和临床信息，有可能识别后续中枢神经系统肿瘤风险高或低的儿童癌症幸存者。这些信息可用于指导监测，以便早期发现后续中枢神经系统肿瘤。
