Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer.
Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer.
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DOI：
10.1200/po.22.00390
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发表时间：
2022-11
影响因子：
4.6
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目前，多种FGFR抑制剂正在进行临床试验，招募患有不同实体肿瘤的成年人，而极少数招募儿童患者。我们确定了儿童癌症中FGFR改变的类型和频率(FGFR1-4)，以便为未来的临床试验设计提供信息。有FGFR改变的肿瘤是从接受定向DNA测序的两个大的儿科实体肿瘤队列中确定的：Dana-Farber/Boston儿童概况研究(n=888)和多机构GAIN/iCAT2(基因组评估改进新疗法)研究(n=571)。我们回顾了1,395例患者的数据(的患者同时参加了这两项研究)，并进一步评估了经肿瘤面板测序确定为FGFR改变的病例。我们确定了41例肿瘤患者存在致癌的FGFR改变。确诊时的中位年龄为8岁(范围6个月-26岁)。诊断包括11例横纹肌肉瘤，9例低级别胶质瘤和17种其他类型的肿瘤。改变包括功能增强序列变异(n=19)、扩增(n=10)、致癌融合(FGFR3：：TACC3[n=3]、FGFR1：：TACC1[n=1]、FGFR1：：Ebf2[n=1]、FGFR1：：CLIP2[n=1]和FGFR2：：CTNNA3[n=1])、致病倾向变异(n=4)、扩增与不确定意义的致病倾向变异(n=1)。在这个队列中，在两个不同的患者中发现了两种新的FGFR1融合，其中一种对FGFR抑制剂有反应。总而言之，在大约3%(41/1,395)的儿童实体肿瘤中发现了激活的FGFR改变，确定了可能符合条件的儿童癌症患者群体，并成为评估FGFR靶向治疗的试验的良好候选者。重要的是，这项研究的基因组和临床数据可以帮助根据《促进儿童治疗和公平研究法案》进行药物开发。
Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of FGFR alterations (FGFR1-4) in pediatric cancers to inform future clinical trial design. Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children's Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed. We identified 41 patients with tumors harboring an oncogenic FGFR alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions (FGFR3::TACC3 [n = 3], FGFR1::TACC1 [n = 1], FGFR1::EBF2 [n = 1], FGFR1::CLIP2 [n = 1], and FGFR2::CTNNA3 [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel FGFR1 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor. In summary, activating FGFR alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act.