IDH-mutant astrocytomas have a more indolent natural history and better prognosis than their IDH-wild type counterparts, but are still graded according to schemes developed prior to the recognition of this type of neoplasm as a distinct entity. Homozygous deletion of CDKN2A has been proposed as a molecular correlate of aggressive behavior in these tumors, and may be incorporated into future grading systems in an effort to improve prognostic stratification. Fluorescence in situ hybridization (FISH) is a common ancillary testing modality used to assess CDKN2A status, but the specifics of how to best interpret FISH results for prognostication of gliomas have not been clearly defined in the literature. To address this issue, we performed a retrospective analysis of prospectively collected CDKN2A FISH data from 108 primary and 43 recurrent IDH-mutant astrocytomas diagnosed between 2007–2020 at the University of Pittsburgh Medical Center. High level CDKN2A homozygous deletion was rare in primary tumors and was identified more frequently in recurrent tumors. Multivariate Cox Proportional-Hazards analysis demonstrated that histologic grade and CDKN2A status are independent predictors of survival, and the prognostic value of CDKN2A is maximized by applying a threshold of ≥ 30% of tumor cells with homozygous deletion by FISH to define a positive result. At this threshold, CDKN2A deletion significantly stratified survival of histologic grade 4 tumors, but grade 2 and 3 tumors rarely exceeded this cutoff value and did not show worse survival. Lower thresholds identified additional lower grade tumors, but were not prognostically useful. Compared to prior studies, the lack of prognostic significance of CDKN2A homozygous deletion by FISH in grade 2–3 IDH-mutant astrocytomas may reflect differences in cohort populations or technical differences between testing modalities. Definitive criteria for determining CDKN2A homozygous deletion by various methodologies will be critical if this is to be included in future grading schemes.

中文翻译：

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通过荧光原位杂交纯合缺失 CDKN2A 可预测 4 级预后，但不能预测 2 或 3 级 IDH 突变星形细胞瘤

IDH 突变型星形细胞瘤比其 IDH 野生型具有更惰性的自然病程和更好的预后，但仍根据在将此类肿瘤识别为独特实体之前制定的方案进行分级。CDKN2A 的纯合缺失已被提议作为这些肿瘤中侵袭行为的分子相关性，并且可能会被纳入未来的分级系统以努力改善预后分层。荧光原位杂交 (FISH) 是用于评估 CDKN2A 状态的常见辅助检测方式，但文献中尚未明确定义如何最好地解释 FISH 结果以预测胶质瘤的细节。为了解决这个问题，我们对 2007 年至 2020 年间在匹兹堡大学医学中心诊断出的 108 例原发性和 43 例复发性 IDH 突变星形细胞瘤前瞻性收集的 CDKN2A FISH 数据进行了回顾性分析。高水平 CDKN2A 纯合缺失在原发性肿瘤中很少见，在复发性肿瘤中更常见。多变量 Cox 比例风险分析表明，组织学分级和 CDKN2A 状态是生存的独立预测因子，通过 FISH 应用 ≥ 30% 纯合缺失肿瘤细胞的阈值来定义阳性结果，CDKN2A 的预后价值最大化。在这个阈值下，CDKN2A 缺失显着区分了组织学 4 级肿瘤的生存率，但 2 级和 3 级肿瘤很少超过这个临界值，并且没有显示出更差的生存率。较低的阈值确定了其他较低级别的肿瘤，但对预后没有用。与先前的研究相比，FISH 在 2-3 级 IDH 突变星形细胞瘤中缺乏 CDKN2A 纯合缺失的预后意义可能反映了队列人群的差异或测试方式之间的技术差异。如果将其包含在未来的分级方案中，那么通过各种方法确定 CDKN2A 纯合缺失的最终标准将是至关重要的。