Cohen Yoram, Merhavi-Shoham Efrat, Avraham-Lubin Bat Chen R, Savetsky Michael, Frenkel Shahar, Pe'er Jacob, Goldenberg-Cohen Nitza
Department of Gynecology, Sheba Medical Center, Tel Hashomer, Israel.
Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5054-6. doi: 10.1167/iovs.09-3617. Epub 2009 May 6.
Many malignancies are known to be associated with abnormal activation of the PI3K-AKT pathway. Recently, a somatic mutation in the AKT1 gene (E17K) was identified in a small proportion of human tumors. This mutation activated AKT1 by means of abnormal membrane recruitment and stimulated downstream signaling. This study was designed to analyze AKT1 mutations in retinoblastoma and gain insights into the role PI3K-AKT pathway plays in the development of this tumor.
Twenty-four samples of retinoblastoma from children were analyzed for mutations in the AKT1, PTEN and K-RAS genes, using a chip-based matrix-assisted laser desorption-time-of-flight (MALDI-TOF) mass spectrometer. Mutations in the PIK3CA gene were analyzed in 16 retinoblastoma samples using direct sequencing.
These results show that the mutation E17K/AKT1 was not detected in the 24 samples of retinoblastoma analyzed. K-RAS mutations were identified in two samples. There were no mutations in any of the other genes analyzed by a mass array system. On direct sequencing of 16 samples for the PIK3CA gene, one sample showed gain of function mutation in exon 9. In another sample, a genetic polymorphism of unknown significance (rs17849079) was detected in exon 20.
Although the PI3K-AKT pathway is known to be dysregulated in retinoblastoma, the low frequency of oncogenic mutations in the AKT1, PIK3CA, and PTEN genes, suggests a different activating mechanism.
已知许多恶性肿瘤与PI3K - AKT通路的异常激活有关。最近，在一小部分人类肿瘤中发现了AKT1基因（E17K）的体细胞突变。该突变通过异常的膜募集激活AKT1并刺激下游信号传导。本研究旨在分析视网膜母细胞瘤中的AKT1突变，并深入了解PI3K - AKT通路在该肿瘤发生发展中的作用。
使用基于芯片的基质辅助激光解吸飞行时间（MALDI - TOF）质谱仪分析24例儿童视网膜母细胞瘤样本中AKT1、PTEN和K - RAS基因的突变情况。使用直接测序法分析16例视网膜母细胞瘤样本中PIK3CA基因的突变情况。
这些结果表明，在分析的24例视网膜母细胞瘤样本中未检测到E17K/AKT1突变。在两个样本中鉴定出K - RAS突变。通过质谱阵列系统分析的其他基因均未发现突变。对16例样本的PIK3CA基因进行直接测序时，一个样本在第9外显子显示功能获得性突变。在另一个样本中，在第20外显子检测到一个意义不明的基因多态性（rs17849079）。
尽管已知PI3K - AKT通路在视网膜母细胞瘤中失调，但AKT1、PIK3CA和PTEN基因中致癌突变的低频率表明存在不同的激活机制。
