Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration [median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031)]. Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

中文翻译：

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表征小儿低级别胶质瘤的时间基因组异质性

最近的发现为儿童低级别胶质瘤 (LGG) 诊断时的基因组景观提供了宝贵的见解，促进了分子靶向治疗。然而，人们对其时间和治疗相关的基因组异质性知之甚少。充分了解儿科 LGG 基因组图谱随时间的演变对于指导有关靶向治疗和复发诊断活检的决策至关重要。对来自初级诊断和后续手术的配对肿瘤样本进行了荧光原位杂交、突变特异性免疫组织化学和/或靶向测序。对来自三个机构的 45 名患者（41 名两标本，四名三标本）的 94 份肿瘤样本进行了检测。BRAF 融合保守，BRAFV600E 突变，和 FGFR1 重排状态分别在 100%、98% 和 96% 的配对标本中观察到。随着时间的推移，没有检测到 IDH1 突变或 NTRK2、MYB 或 MYBL1 重排的丢失或增加。所有肿瘤的组织学诊断均相同，没有获得性 H3K27M 突变或恶变。11 名患者 (42%) 发生复发时 CDKN2A 缺失状态的变化，其中 7 名获得半合子 CDKN2A 缺失，4 名丢失。与没有获得这种改变的患者相比，获得性 CDKN2A 缺失的患者的进展时间和后续手术时间较短 [进展时间中位数：5.5 个月与 16.0 个月 (p = 0.048)；下一次手术的中位时间：17.0 个月与 29.0 个月 (p = 0.031)]。儿科 LGG 中最有针对性的遗传畸变，包括 BRAF 改变，在复发和化疗或放疗后是保守的。然而，CDKN2A 缺失状态随时间的变化得到了证明。CDKN2A 缺失的获得可能定义了预后较差的儿科 LGG 的高风险亚组。鉴于 CDKN2A 缺失肿瘤靶向治疗的潜力，某些患者可能需要在复发时进行活检，尤其是那些进展迅速的患者。