Summers Ryan J, Castellino Sharon M, Porter Christopher C, MacDonald Tobey J, Basu Gargi D, Szelinger Szabolcs, Bhasin Manoj K, Cash Thomas, Carter Alexis B, Castellino Robert Craig, Fangusaro Jason R, Mitchell Sarah G, Pauly Melinda G, Pencheva Bojana, Wechsler Daniel S, Graham Douglas K, Goldsmith Kelly C
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University, Atlanta, GA.
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
JCO Precis Oncol. 2022 Apr;6:e2100451. doi: 10.1200/PO.21.00451.
Profiling of pediatric cancers through deep sequencing of large gene panels and whole exomes is rapidly being adopted in many clinical settings. However, the most impactful approach to genomic profiling of pediatric cancers remains to be defined.
We conducted a prospective precision medicine trial, using whole-exome sequencing of tumor and germline tissue and whole-transcriptome sequencing (RNA Seq) of tumor tissue to characterize the mutational landscape of 127 tumors from 126 unique patients across the spectrum of pediatric brain tumors, hematologic malignancies, and extracranial solid tumors.
We identified somatic tumor alterations in 121/127 (95.3%) tumor samples and identified cancer predisposition syndromes on the basis of known pathogenic or likely pathogenic germline mutations in cancer predisposition genes in 9/126 patients (7.1%). Additionally, we developed a novel scoring system for measuring the impact of tumor and germline sequencing, encompassing therapeutically relevant genomic alterations, cancer-related germline findings, recommendations for treatment, and refinement of risk stratification or prognosis. At least one impactful finding from the genomic results was identified in 108/127 (85%) samples sequenced. A recommendation to consider a targeted agent was provided for 82/126 (65.1%) patients. Twenty patients ultimately received therapy with a molecularly targeted agent, representing 24% of those who received a targeted agent recommendation and 16% of the total cohort.
Paired tumor/normal whole-exome sequencing and tumor RNA Seq of de novo or relapsed/refractory tumors was feasible and clinically impactful in high-risk pediatric cancer patients.
通过对大基因面板和全外显子组进行深度测序来分析儿童癌症，这种方法正在许多临床环境中迅速得到应用。然而，对儿童癌症进行基因组分析的最有效方法仍有待确定。
我们开展了一项前瞻性精准医学试验，利用肿瘤和种系组织的全外显子组测序以及肿瘤组织的全转录组测序（RNA测序）来描绘126名独特患者的127个肿瘤的突变图谱，这些肿瘤涵盖了儿童脑肿瘤、血液系统恶性肿瘤和颅外实体瘤。
我们在121/127（95.3%）的肿瘤样本中鉴定出体细胞肿瘤改变，并在9/126（7.1%）的患者中，基于癌症易感基因中已知的致病或可能致病的种系突变，鉴定出癌症易感综合征。此外，我们开发了一种新的评分系统，用于衡量肿瘤和种系测序的影响，该系统涵盖治疗相关的基因组改变、与癌症相关的种系发现、治疗建议以及风险分层或预后的优化。在测序的108/127（85%）样本中鉴定出至少一项来自基因组结果的有影响力的发现。为82/126（65.1%）的患者提供了考虑使用靶向药物的建议。最终有20名患者接受了分子靶向药物治疗，占接受靶向药物建议患者的24%和整个队列的16%。
对初发或复发/难治性肿瘤进行配对的肿瘤/正常全外显子组测序和肿瘤RNA测序，在高危儿童癌症患者中是可行的且具有临床意义。
