Alterations in the RB1 Pathway in Low-grade Diffuse Gliomas Lacking Common Genetic Alterations
Alterations in the RB1 Pathway in Low-grade Diffuse Gliomas Lacking Common Genetic Alterations
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DOI：
10.1111/j.1750-3639.2011.00492.x
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发表时间：
2011-11-01
期刊：
影响因子：
6.4
通讯作者：
Ohgaki, Hiroko
中科院分区：
文献类型：
--
作者：
Kim, Young-Ho;Lachuer, Joel;Ohgaki, Hiroko
我们最近报道，绝大多数(>；90%)低级别弥漫性胶质瘤(弥漫性星形细胞瘤、寡星形细胞瘤和少突胶质细胞瘤)至少携带以下一种基因改变：IDH1/2突变、TP53突变或1p/19q丢失。只有7%的病例是三重阴性(即缺乏这些变化中的任何一种)。对15例WHO II级三阴性胶质瘤(8例弥漫性星形细胞瘤和7例少突胶质细胞瘤)进行阵列比较基因组杂交(CGH)，发现3例缺失9p21(ARF)，3例缺失p15(INK4b)，2例缺失13q14-13q32(含RB1)。对31例三阴性病例和16 0例非三阴性病例的进一步分析发现，三阴性病例中RB1通路的改变(p15INK4b、p16INK4a和rb1基因的纯合子缺失和启动子甲基化)的发生率(26%)显著高于非三阴性病例(11%；P=0.0371)。调整年龄、组织学和治疗后的多因素分析显示，RB1通路改变与低级别弥漫性胶质瘤患者的不良预后显著相关[风险比，3.024(1.279-6.631)；P=0.0057]。这些结果表明，部分缺乏常见遗传改变的低级别弥漫性胶质瘤可能通过不同的遗传途径发展，其中可能包括失去由RB1途径调控的细胞周期控制。
We recently reported that the vast majority (>90%) of low-grade diffuse gliomas (diffuse astrocytoma, oligoastrocytoma and oligodendroglioma) carry at least one of the following genetic alterations: IDH1/2 mutation, TP53 mutation or 1p/19q loss. Only 7% of cases were triple-negative (ie, lacking any of these alterations). In the present study, array comparative genomic hybridization (CGH) in 15 triple-negative WHO grade II gliomas (eight diffuse astrocytomas and seven oligodendrogliomas) showed loss at 9p21 (p14(ARF), p15(INK4b), p16(INK4a) loci) and 13q14-13q32 (containing the RB1 locus) in three and two cases, respectively. Further analyses in 31 triple-negative cases as well as a total of 160 non-triple-negative cases revealed that alterations in the RB1 pathway (homozygous deletion and promoter methylation of the p15INK4b, p16INK4a and RB1 genes) were significantly more frequent in triple-negative (26%) than in non-triple-negative cases (11%; P = 0.0371). Multivariate analysis after adjustment for age, histology and treatment showed that RB1 pathway alterations were significantly associated with unfavorable outcome for patients with low-grade diffuse glioma [hazard ratio, 3.024 (1.279-6.631); P = 0.0057]. These results suggest that a fraction of low-grade diffuse gliomas lacking common genetic alterations may develop through a distinct genetic pathway, which may include loss of cell-cycle control regulated by the RB1 pathway.