Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone, Marseille, France.
Acta Neuropathol. 2010 Dec;120(6):719-29. doi: 10.1007/s00401-010-0777-8. Epub 2010 Nov 16.
The phenotypic heterogeneity of low-grade gliomas (LGGs) is still inconsistently explained by known molecular abnormalities in patients treated according to the present standards of care. IDH1 codon 132 and IDH2 codon 172 sequencing was performed in a series of 47 LGGs and correlated with clinical presentation, MR imaging characteristics, genomic profile and outcome. A total of 38 IDH1 mutations at codon 132 and 2 IDH2 mutations at codon 172 were found, including 35 R132H (87.5%), 2 R132C (5.0%), 1 R132S (2.5%) and 2 R172 M (5%). The IDH mutations were significantly associated with 1p19q deleted genotype (P = 0.031) and p53 expression (P = 0.014). The presence (vs. absence) of IDH mutations was associated with a better outcome (5-year survival rate, 93% vs. 51%, respectively, P = 0.000001). After adjustment for age, tumor location and size, radiologic infiltration pattern and extent of surgery, multivariate analysis confirmed that IDH mutations was an independent favorable prognostic factor (hazard ratio = 40.9; 95% CI, 2.89-578.49, P = 0.006). Furthermore, we showed that patients with IDH-nonmutated tumors were significantly older (P = 0.020) and that these tumors involved significantly more frequently the insula (P = 0.004), were larger in size (>6 cm, P = 0.047), displayed an infiltrative pattern on MRI (P = 0.007) and were all p53 negative with no 1p19q deletion (P < 10⁻⁶). The absence of IDH mutations in LGGs identifies a novel entity of LGGs with distinctive location, infiltrative behavior, specific molecular alterations, and dismal outcome. These findings could significantly modify the LGG classification and may represent a new tool to guide patient-tailored therapy.
低级别胶质瘤（LGG）的表型异质性仍然无法用目前治疗标准下患者已知的分子异常来解释。对 47 例 LGG 进行了 IDH1 密码子 132 和 IDH2 密码子 172 的测序，并与临床表现、MR 成像特征、基因组谱和预后相关联。在总共 38 个 IDH1 突变位于密码子 132，2 个 IDH2 突变位于密码子 172，包括 35 个 R132H（87.5%）、2 个 R132C（5.0%）、1 个 R132S（2.5%）和 2 个 R172 M（5%）。IDH 突变与 1p19q 缺失基因型（P = 0.031）和 p53 表达（P = 0.014）显著相关。存在（与不存在）IDH 突变与更好的预后相关（5 年生存率分别为 93%和 51%，P = 0.000001）。在调整年龄、肿瘤位置和大小、放射学浸润模式和手术范围后，多变量分析证实 IDH 突变是一个独立的有利预后因素（危险比= 40.9；95%置信区间，2.89-578.49，P = 0.006）。此外，我们表明，IDH 非突变肿瘤的患者年龄明显较大（P = 0.020），这些肿瘤更频繁地累及岛叶（P = 0.004），体积较大（>6cm，P = 0.047），MRI 上呈浸润性模式（P = 0.007），并且均为 p53 阴性，无 1p19q 缺失（P < 10⁻⁶）。LGG 中 IDH 突变的缺失确定了 LGG 的一种新实体，具有独特的位置、浸润性行为、特定的分子改变和不良的预后。这些发现可能会显著改变 LGG 的分类，并可能成为指导个体化治疗的新工具。
