Haluska Frank G, Tsao Hensin, Wu Helen, Haluska Frank S, Lazar Alexander, Goel Vikas
Division of Hematology/Oncology, Massashusetts General Hospital, Boston, Massachusetts, USA.
Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2301s-2307s. doi: 10.1158/1078-0432.CCR-05-2518.
Alterations in the RAS signaling cascade are almost uniformly present in melanoma. RAS itself is only infrequently mutated in melanoma although downstream of RAS lie BRAF on the mitogen-activated protein kinase pathway and PTEN on the protein kinase B/Akt pathway. These genes are often altered in melanomas; indeed, the most frequent target of mutation in melanomas is BRAF, which is mutated in approximately 60% to 70% of superficial spreading melanomas. These mutations occur in a background that is not normal, with the CDKN2A locus also typically being mutated. We review herein the data that suggest that the distribution of the signaling mutations is important. In general, melanomas carry a mutated NRAS, a mutated BRAF, or concurrent BRAF and PTEN mutations. These data support the hypothesis that the biochemical functions of RAS are portioned by mutations in the pathways lying downstream. Moreover, these mutations have no apparent relationship to the patterns of alteration of CDKN2A and its downstream effectors. Thus, the data also suggest that successful exploitation of mutations in melanoma will be dependent on understanding not only mutations and their frequency but their genetic context as well.
RAS信号级联的改变在黑色素瘤中几乎普遍存在。RAS自身在黑色素瘤中很少发生突变，尽管在RAS下游的丝裂原活化蛋白激酶途径上有BRAF，在蛋白激酶B/Akt途径上有PTEN。这些基因在黑色素瘤中经常发生改变；事实上，黑色素瘤中最常见的突变靶点是BRAF，在大约60%至70%的浅表扩散性黑色素瘤中发生突变。这些突变发生在不正常的背景下，CDKN2A基因座通常也会发生突变。我们在此回顾表明信号突变分布很重要的数据。一般来说，黑色素瘤携带NRAS突变、BRAF突变或BRAF与PTEN同时突变。这些数据支持这样的假说，即RAS的生化功能由下游途径中的突变进行分配。此外，这些突变与CDKN2A及其下游效应器的改变模式没有明显关系。因此，数据还表明，成功利用黑色素瘤中的突变将不仅取决于了解突变及其频率，还取决于了解它们的遗传背景。
