Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas
Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas
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DOI：
10.1038/labinvest.3700223
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发表时间：
2005-02-01
影响因子：
5
通讯作者：
Konishi, N
中科院分区：
文献类型：
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作者：
Nakamura, M;Ishida, E;Konishi, N
胶质瘤中22号染色体长臂（22 q）上频繁的等位基因丢失表明该位置存在肿瘤抑制基因（TSG）。然而，位于该染色体中的靶基因仍然是未知的，并且它们在星形细胞肿瘤，特别是继发性胶质母细胞瘤的发展中的假定作用尚未确定。为了对星形细胞肿瘤中常见的缺失区域进行精确的物理图谱，我们使用31个多态性微卫星标记对一系列II级弥漫性星形细胞瘤、间变性星形细胞瘤、原发性胶质母细胞瘤和从低级别星形细胞瘤演变而来的继发性胶质母细胞瘤进行了22 q的高密度杂合性丢失（洛H）分析。33%（12/36）的弥漫性星形细胞瘤、40%（4/10）的间变性星形细胞瘤、41%（26/64）的原发性胶质母细胞瘤和82%（23/28）的继发性胶质母细胞瘤存在一个或多个位点的洛缺失。在原发性胶质母细胞瘤中22 q缺失的表征确定了22 q12.3 - 13.2和22 q13.31处的两个最小缺失区域位点。有趣的是，23例继发性胶质母细胞瘤中有22例在22q12.3的同一个小区域（957 kb）缺失，该区域是人类组织金属蛋白酶抑制剂-3（TIMP-3）的所在区域。对该基因启动子甲基化和表达的研究表明，在继发性胶质母细胞瘤中，频繁的甲基化与TIMP-3表达的缺失相关。这种表观遗传学改变与8例II级弥漫性星形细胞瘤患者的生存率低显著相关。我们的研究结果表明，一个957 kb的基因座，位于22q12.3，可能包含推定的TSG，TIMP-3，这似乎是相关的进展，以继发性胶质母细胞瘤，随后的II级弥漫性星形细胞瘤的预后。此外，不能排除22q12.3 - 13.2和22q13.31上其他推定的TSG也可能参与原发性胶质母细胞瘤的发生的可能性。
Frequent allelic losses on the long arm of chromosome 22 (22q) in gliomas indicate the presence of tumor suppressor gene (TSG) at this location. However, the target gene(s) residing in this chromosome are still unknown and their putative roles in the development of astrocytic tumors, especially in secondary glioblastoma, have not yet been defined. To compile a precise physical map for the region of common deletions in astrocytic tumors, we performed a high-density loss of heterozygosity (LOH) analysis using 31 polymorphic microsatellite markers spanning 22q in a series of grade II diffuse astrocytomas, anaplastic astrocytomas, primary glioblastomas, and secondary glioblastomas that had evolved from lower grade astrocytomas. LOH was found at one or more loci in 33% (12/36) of grade II diffuse astrocytomas, in 40% (4/10) of anaplastic astrocytomas, in 41% (26/64) of primary glioblastomas, and in 82% (23/28) of secondary glioblastomas. Characterization of the 22q deletions in primary glioblastomas identified two sites of minimally deleted regions at 22q12.3 - 13.2 and 22q13.31. Interestingly, 22 of 23 secondary glioblastomas affected shared a deletion in the same small ( 957 kb) region of 22q12.3, a region in which the human tissue inhibitor of metalloproteinases-3 (TIMP-3) is located. Investigation of the promoter methylation and expression of this gene indicated that frequent hypermethylation correlated with loss of TIMP-3 expression in secondary glioblastoma. This epigenetic change was significantly correlated to poor survival in eight patients with grade II diffuse astrocytoma. Our results suggest that a 957 kb locus, located at 22q12.3, may contain the putative TSG, TIMP-3, that appears to be relevant to progression to secondary glioblastoma and subsequently to the prognosis of grade II diffuse astrocytoma. In addition, the possibility of other putative TSGs on 22q12.3 - 13.2 and 22q13.31 that may also be involved in the development of primary glioblastomas cannot be ruled out.