Jeuken Judith, van den Broecke Caroline, Gijsen Sabine, Boots-Sprenger Sandra, Wesseling Pieter
Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500, Nijmegen, The Netherlands.
Acta Neuropathol. 2007 Aug;114(2):121-33. doi: 10.1007/s00401-007-0239-0. Epub 2007 Jun 23.
Aberrant RAS/RAF signaling has been reported to be important for many tumor types including gliomas. Activation of the RAS/RAF pathway can result from oncogenic mutations of RAS/RAF itself. However, such mutations have only occasionally been reported in gliomas. In order to further elucidate the role of RAS/RAF pathway activation in a histopathological and genetic spectrum of glioma subtypes (n = 93), we evaluated different types of aberrations in this pathway. Hotspot mutation analysis of BRAF, NRAS, KRAS, and HRAS revealed only two mutations, V600M in BRAF and G10E in NRAS, both occurring in pure oligodendroglial tumors. However, CGH analysis of 87 tumors revealed copy number gains including the above mentioned oncogenes in 38 of the neoplasms (44%) and including the upstream growth factors EGF, PDGF, IGF, FGF, TGF and/or their receptors in 46 tumors (53%). Phosphorylated MAPK (i.e. the activated compound downstream the RAS/RAF pathway) was detected by immunohistochemistry using tissue micro-arrays in the majority of gliomas. Interestingly, a significant correlation was found for nuclear MAPK-P staining and the number of these copy number gains (<or= 2 and >or= 3). These results indicate that RAS/RAF pathway activation in gliomas is achieved much more frequently by copy number gains including RAS/RAF and/or upstream growth factor (receptor) than by activating RAS/RAF mutations.
据报道，异常的RAS/RAF信号传导对包括神经胶质瘤在内的多种肿瘤类型都很重要。RAS/RAF途径的激活可能源于RAS/RAF自身的致癌突变。然而，此类突变在神经胶质瘤中仅偶尔被报道。为了进一步阐明RAS/RAF途径激活在神经胶质瘤亚型（n = 93）的组织病理学和基因谱中的作用，我们评估了该途径中不同类型的畸变。对BRAF、NRAS、KRAS和HRAS的热点突变分析仅发现两个突变，即BRAF中的V600M和NRAS中的G10E，二者均发生在纯少突胶质细胞瘤中。然而，对87个肿瘤的比较基因组杂交（CGH）分析显示，38个肿瘤（44%）存在包括上述致癌基因在内的拷贝数增加，46个肿瘤（53%）存在包括上游生长因子EGF、PDGF、IGF、FGF、TGF和/或其受体在内的拷贝数增加。使用组织微阵列通过免疫组织化学在大多数神经胶质瘤中检测到磷酸化的MAPK（即RAS/RAF途径下游的活化化合物）。有趣的是，发现核MAPK-P染色与这些拷贝数增加的数量（≤2和≥3）之间存在显著相关性。这些结果表明，在神经胶质瘤中，RAS/RAF途径的激活更多是通过包括RAS/RAF和/或上游生长因子（受体）在内的拷贝数增加实现的，而非通过激活RAS/RAF突变。
