Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma.
Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma.
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DOI：
10.1158/0008-5472.can-08-3272
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发表时间：
2008-12-15
期刊：
影响因子：
11.2
通讯作者：
Waldman T
中科院分区：
文献类型：
--
作者：
Solomon DA;Kim JS;Cronin JC;Sibenaller Z;Ryken T;Rosenberg SA;Ressom H;Jean W;Bigner D;Yan H;Samuels Y;Waldman T
CDKN2A/B基因在染色体9p端粒上有一个额外的肿瘤抑制基因，长期以来一直被认为存在。应用Affymetrix 250K单核苷酸多态芯片检测多形性胶质母细胞瘤(GBM)中PTPRD基因的高频率缺失，该基因编码位于染色体9p23-24.1的受体蛋白酪氨酸磷酸酶。在缺乏缺失的样本子集中发现了PTPRD的错义和无义突变，包括一个带有野生型等位基因体细胞丢失的遗传性突变。然后，我们对黑色素瘤的基因进行了测序，并在57个肿瘤中的7个(12%)中确定了10个体细胞突变。PTPRD在含有缺失或突变的GBM和黑色素瘤细胞中的表达重建导致生长抑制和细胞凋亡，而体细胞和结构突变都减轻了这一现象。这些数据表明PTPRD与神经外胚层起源的肿瘤的发病机制有关，当与最近关于结肠癌和肺腺癌中PTPRD突变的其他报道相结合时，表明PTPRD可能是在广泛的人类常见肿瘤类型中失活的一组肿瘤抑制基因之一。
An additional tumor suppressor gene on chromosome 9p telomeric to the CDKN2A/B locus has long been postulated to exist. Using Affymetrix 250K single nucleotide polymorphism arrays to screen for copy number changes in glioblastoma multiforme (GBM), we detected a high frequency of deletions of the PTPRD gene, which encodes a receptor protein tyrosine phosphatase at chromosome 9p23-24.1. Missense and nonsense mutations of PTPRD were identified in a subset of the samples lacking deletions, including an inherited mutation with somatic loss of the wild-type allele. We then sequenced the gene in melanoma and identified 10 somatic mutations in 7 of 57 tumors (12%). Reconstitution of PTPRD expression in GBM and melanoma cells harboring deletions or mutations led to growth suppression and apoptosis that was alleviated by both the somatic and constitutional mutations. These data implicate PTPRD in the pathogenesis of tumors of neuroectodermal origin and, when taken together with other recent reports of PTPRD mutations in adenocarcinoma of the colon and lung, suggest that PTPRD may be one of a select group of tumor suppressor genes that are inactivated in a wide range of common human tumor types.