PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas
PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas
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DOI：
10.1101/gad.1972310
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发表时间：
2010-10-01
影响因子：
10.5
通讯作者：
Holland, Eric C.
中科院分区：
文献类型：
--
作者：
Ozawa, Tatsuya;Brennan, Cameron W.;Holland, Eric C.
以基因内缺失形式的基因重排是胶质瘤中表皮生长因子受体（EGFR）基因致癌突变的主要机制。然而，血小板源性生长因子受体α（PDGFRA）基因重排在这些肿瘤中的发生率尚不清楚。我们研究了PDGFRA扩增的胶质瘤中的PDGFRA位点，并确定了两种重排，包括第一例激酶插入结构域受体（KDR）（VEGFRII）和PDGFRA基因之间的基因融合，以及6例PDGFRA（Delta 8，9），基因内缺失重排。PDGFRA（Delta 8，9）突变体是常见的，存在于40%的多形性胶质母细胞瘤（GBM）与PDGFRA扩增。具有这两种类型PDGFRA重排的肿瘤显示少突胶质细胞瘤的组织学特征，并且这两种重排的基因产物显示组成性升高的酪氨酸激酶活性和转化潜力，其被PDGFR阻断逆转。这些结果表明，这些PDGFRA突变体的可能性，在这个子集的胶质瘤的癌基因的行为，这种重排的患病率可能被大大低估。
Gene rearrangement in the form of an intragenic deletion is the primary mechanism of oncogenic mutation of the epidermal growth factor receptor (EGFR) gene in gliomas. However, the incidence of platelet-derived growth factor receptor-alpha (PDGFRA) gene rearrangement in these tumors is unknown. We investigated the PDGFRA locus in PDGFRA-amplified gliomas and identified two rearrangements, including the first case of a gene fusion between kinase insert domain receptor (KDR) (VEGFRII) and the PDGFRA gene, and six cases of PDGFRA(Delta 8, 9), an intragenic deletion rearrangement. The PDGFRA(Delta 8, 9) mutant was common, being present in 40% of the glioblastoma multiformes (GBMs) with PDGFRA amplification. Tumors with these two types of PDGFRA rearrangement displayed histologic features of oligodendroglioma, and the gene products of both rearrangements showed constitutively elevated tyrosine kinase activity and transforming potential that was reversed by PDGFR blockade. These results suggest the possibility that these PDGFRA mutants behave as oncogenes in this subset of gliomas, and that the prevalence of such rearrangements may have been considerably underestimated.