Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma.
Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma.
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儿童毛粘液样星形细胞瘤中的双重激活FGFR1突变
DOI：
10.1002/mgg3.1597
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发表时间：
2021-03
影响因子：
2
通讯作者：
Erson-Omay EZ
中科院分区：
文献类型：
--
作者：
Fomchenko EI;Reeves BC;Sullivan W;Marks AM;Huttner A;Kahle KT;Erson-Omay EZ
毛粘液样星形细胞瘤是星形细胞瘤的一种侵袭性亚型，不经WHO分级，常位于下丘脑/视交叉区，累及间脑结构，具有生存期短和复发率高的特点。毛粘液样星形细胞瘤的治疗仍存在争议，病理组织诊断和减轻肿块效应是手术的主要目标，同时避免治疗相关的发病率，包括视力丧失、全垂体功能减退和下丘脑功能障碍。所有儿科患者的化疗（通常为长春新碱和卡铂）和5岁以上儿科患者的放疗均用于治疗。我们报告了一个未完全切除的毛粘液样星形细胞瘤患儿的临床表现、手术治疗和全外显子组测序结果。我们鉴定了两个影响FGFR 1的体细胞激活错义突变，包括FGFR 1 p.K656E和FGFR 1 p.V561M。虽然前者是一种已知的热点突变，既激活又转化，但后者已被描述为赋予对FGFR抑制剂的抗性的看门突变。有趣的是，这两种突变在肿瘤内以相似的变体等位基因频率存在。我们患者肿瘤中FGFR 1 p.K656E和FGFR 1 p.V561M突变的相似变异等位基因频率表明这些突变可能发生在相似的时间点。除了STAT 3或PI 3 K/mTOR抑制剂之外，使用FGFR抑制剂可能证明是靶向我们患者的毛粘液样星形细胞瘤的有用策略。毛粘液样星形细胞瘤是星形细胞瘤的一种侵袭性亚型，未被WHO分级，常位于下丘脑/视交叉区域，影响间脑结构，其特征是生存期短和复发率高;其治疗仍有争议。我们描述一个儿童患者的毛粘液样星形细胞瘤。我们鉴定了一个已知的热点突变FGFR 1 p.K656E，它既是激活的又是转化的，以及一个看门突变FGFR 1 p.V561M，它赋予对FGFR抑制剂的抗性。除了STAT 3或PI 3 K/mTOR抑制剂之外，使用FGFR抑制剂可能证明是靶向我们患者的毛粘液样星形细胞瘤的有用策略。
Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma, not graded by WHO, frequently located in hypothalamic/chiasmatic region, affecting diencephalic structures, and characterized by shorter survival and high recurrence rates. Pilomyxoid astrocytoma management remains controversial, with pathologic tissue diagnosis and relief of mass effect being the main goals of surgery while avoiding treatment‐related morbidity, including vision loss, panhypopituitarism, and hypothalamic dysfunction. Chemotherapy (typically vincristine and carboplatin) in all pediatric patients and radiation therapy in pediatric patients over 5 years of age are used for treatment. We report clinical presentation, surgical management, and whole exome sequencing results in a pediatric patient with the subtotally resected pilomyxoid astrocytoma. We identified two somatic activating missense mutations affecting FGFR1, including FGFR1 p.K656E and FGFR1 p.V561M. While the former is a known hotspot mutation that is both activating and transforming, the latter has been described as a gatekeeper mutation imparting resistance to FGFR inhibitors. Interestingly, both mutations were present with similar variant allele frequency within the tumor. Similar variant allele frequencies of FGFR1 p.K656E and FGFR1 p.V561M mutations in our patient's tumor suggest that these mutations may have occurred at similar time points. Use of FGFR inhibitors in addition to STAT3 or PI3K/mTOR inhibition may prove a useful strategy in targeting our patient's pilomyxoid astrocytoma. Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma, not graded by WHO, frequently located in hypothalamic/chiasmatic regions, affecting diencephalic structures, and characterized by shorter survival and high recurrence rates; their management remains controversial. We describe a pediatric patient with a pilomyxoid astrocytoma. We identified a known hotspot mutation FGFR1 p.K656E that is both activating and transforming, and a gatekeeper mutation FGFR1 p.V561M imparting resistance to FGFR inhibitors. Use of FGFR inhibitors in addition to STAT3 or PI3K/mTOR inhibition may prove a useful strategy in targeting our patient's pilomyxoid astrocytoma.
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