Identification of Hedgehog pathway responsive glioblastomas by isocitrate dehydrogenase mutation.
Identification of Hedgehog pathway responsive glioblastomas by isocitrate dehydrogenase mutation.
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DOI：
10.1016/j.canlet.2012.10.002
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发表时间：
2013-01-28
期刊：
影响因子：
9.7
通讯作者：
Cooper, Michael K.
中科院分区：
文献类型：
--
作者：
Valadez, J. Gerardo;Grover, Vandana K.;Carter, Melissa D.;Calcutt, M. Wade;Abiria, Sunday A.;Lundberg, Christopher J.;Williams, Thomas V.;Cooper, Michael K.
Hedgehog （Hh）通路调节成人胶质瘤的一个亚群的生长，更好地定义Hh应答亚型可以增强在患者中监测和靶向该通路的临床效用。异柠檬酸脱氢酶（IDH）基因的体细胞突变经常发生在WHO II级和III级胶质瘤和WHO IV级继发性胶质母细胞瘤中。Hh通路在WHO II级和III级胶质瘤中的激活表明，它可能也适用于从较低级别病变发展而来的胶质母细胞瘤。为了评估这种可能性，并更好地定义Hh反应的分子和组织病理学胶质瘤亚型，研究人员对成人胶质瘤标本中的IDH基因进行了测序，以确定Hh通路的操作性。II-IV级IDH突变标本的比例与Hh基因靶PTCH1表达水平升高的比例相关。在所有原代培养物和来自idh突变胶质瘤标本（包括idh突变胶质瘤）的异种移植物中测量了操作Hh通路的指数。相比之下，Hh通路在缺乏IDH突变或既往低级别疾病史的胶质母细胞瘤中不起作用。然而，操作通路并不需要IDH突变，因为在具有野生型IDH序列的III级胶质瘤中也检测到显著的Hh通路调节。这些结果表明Hh通路在II级和III级胶质瘤和胶质母细胞瘤中起作用，具有从低级别胶质瘤进化而来的分子或组织病理学证据。最后，这些发现表明胶质瘤共享这种分子定义的进展途径出现在hh反应细胞类型中。
The Hedgehog (Hh) pathway regulates the growth of a subset of adult gliomas and better definition of Hh-responsive subtypes could enhance the clinical utility of monitoring and targeting this pathway in patients. Somatic mutations of the isocitrate dehydrogenase (IDH) genes occur frequently in WHO grades II and III gliomas and WHO grade IV secondary glioblastomas. Hh pathway activation in WHO grades II and III gliomas suggests that it might also be operational in glioblastomas that developed from lower grade lesions. To evaluate this possibility and to better define the molecular and histopathological glioma subtypes that are Hh-responsive, IDH genes were sequenced in adult glioma specimens assayed for an operant Hh pathway. The proportions of grades II–IV specimens with IDH mutations correlated with the proportions that expressed elevated levels of the Hh gene target PTCH1. Indices of an operational Hh pathway were measured in all primary cultures and xenografts derived from IDH-mutant glioma specimens, including IDH-mutant glioblastomas. In contrast, the Hh pathway was not operational in glioblastomas that lacked IDH mutation or history of antecedent lower-grade disease. IDH mutation is not required for an operant pathway however, as significant Hh pathway modulation was also measured in grade III gliomas with wild-type IDH sequences. These results indicate that the Hh pathway is operational in grades II and III gliomas and glioblastomas with molecular or histopathological evidence for evolvement from lower-grade gliomas. Lastly, these findings suggest that gliomas sharing this molecularly defined route of progression arise in Hh-responsive cell types.
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影响因子：
12.7
作者：
Hartmann, Christian;Meyer, Jochen;von Deimling, Andreas
通讯作者：
von Deimling, Andreas
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.2
作者：
Bar, Eli E.;Chaudhry, Aneeka;Eberharta, Charles G.
通讯作者：
Eberharta, Charles G.
DOI：
10.1073/pnas.1101657108
发表时间：
2011-03-15
影响因子：
11.1
作者：
Monje, Michelle;Mitra, Siddhartha S.;Beachy, Philip A.
通讯作者：
Beachy, Philip A.
影响因子：
50.3
作者：
Phillips, HS;Kharbanda, S;Aldape, K
通讯作者：
Aldape, K