Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIk3CA amplification in gastric carcinoma
Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIk3CA amplification in gastric carcinoma
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DOI：
10.1002/ijc.10962
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发表时间：
2003-04-10
影响因子：
6.4
通讯作者：
Chi, SG
中科院分区：
文献类型：
--
作者：
Byun, DS;Cho, K;Chi, SG
已在许多类型的人类癌症中观察到分别负性和正性调节PI 3-激酶活性的PTEN和PIK 3CA的突变改变。为了探讨PTEN和PIK 3CA突变在胃肿瘤发生中的意义，我们分析了126例胃组织和15个细胞系中PTEN和PIK 3CA基因的表达和突变状态。15个细胞系中有5个（33%）和55个原发癌中有20个（36%）表达异常低，而包括16个良性肿瘤在内的71个非癌组织中0个表达异常。利用基因内多态性（IVS 4 +109）进行等位基因分型分析，发现30例有信息的病例中有14例（47%）携带该基因的洛，这与低表达密切相关。晚期肿瘤中的洛缺失率[19例中的12例（63%）]显著高于早期肿瘤[11例中的2例（18%）]，低分化肿瘤中的杂合性缺失率[13例中的9例（69%）]高于高分化或中分化肿瘤[17例中的5例（29%）]。然而，有趣的是，没有一个洛肿瘤携带其余等位基因的突变破坏，表明在胃肿瘤发生中PTEN的单倍不足。甲基化研究显示，在细胞系和原发性肿瘤中，PTEN假基因而不是PTEN被甲基化，这表明PTEN不是胃癌中表观遗传沉默的靶点，并且在PTEN启动子的甲基化分析中应更仔细地考虑假基因。在15个细胞系中的9个（60%）和55个原发性肿瘤中的20个（36.4%）中发现PIK 3CA基因组扩增，但在非癌组织中没有发现。此外，PIK 3CA扩增主要在没有PTEN改变的肿瘤中检测到，表明PTEN和PIK 3CA的突变在胃肿瘤发生中是相互排斥的事件。PIK 3CA的扩增与PIK 3CA转录物的表达增加和磷酸化AKT水平升高密切相关。总的来说，我们的数据显示，15个胃细胞系中的13个（87%）和55个原发性癌中的31个（56%）具有PIK 3CA扩增或PTEN异常减少。PTEN和PIK 3CA的互斥改变也表明，任一基因的突变都可以激活PI 3-激酶/AKT信号通路，这与胃肿瘤细胞的恶性进展直接相关。(C)2003 Wiley-Liss，Inc.
Mutational alterations of PTEN and PIK3CA, which negatively and positively regulate PI3-kinase activity, respectively, have been observed in many types of human cancer. To explore the implication of PTEN and PIK3CA mutations in gastric tumorigenesis, we characterized the expression and mutation status of the genes in 126 gastric tissues and 15 cell lines. Expression of PTEN transcript was abnormally low in 5 of 15 (33%) cell lines and 20 of 55 (36%) primary carcinomas, whereas 0 of 71 noncancerous tissues including 16 benign tumors showed altered expression. Allelotyping analysis using an intragenic polymorphism (IVS4+109) revealed that 14 of 30 (47%) informative cases carried LOH of the gene, which is closely linked to low expression. The LOH rate was significantly higher in advanced tumors [ 12 of 19 (63%)] compared to early-stage tumors [2 of 11 (18%)] and more frequent in poorly differentiated tumors [9 of 13 (69%)] than well- or moderately differentiated tumors [5 of 17 (29%)]. Interestingly, however, none of the LOH tumors carried mutational disruption of the remaining allele, suggesting haploinsufficiency of PTEN in gastric tumorigenesis. Methylation studies revealed that PTEN pseudogene, but not PTEN, is methylated in cell lines and primary tumors, indicating that PTEN is not a target of epigenetic silencing in gastric cancers and that the pseudogene should be considered more carefully in methylation analysis of the PTEN promoter. Genomic amplification of PIK3CA was found in 9 of 15 (60%) cell lines and 20 of 55 (36.4%) primary tumors but in no noncancerous tissues. Furthermore, PIK3CA amplification was predominantly detected in tumors with no PTEN alterations, suggesting that mutations of PTEN and PIK3CA are mutually exclusive events in gastric tumorigenesis. Amplification of PIK3CA was strongly associated with increased expression of PIK3CA transcript and elevated levels of phospho-AKT. Collectively, our data reveal that 13 of 15 (87%) gastric cell lines and 31 of 55 (56%) primary carcinomas harbored either amplification of PIK3CA or abnormal reduction of PTEN. Mutually exclusive alterations of PTEN and PIK3CA also suggest that mutations of either gene could activate the PI3-kinase/AKT signaling pathway, which is directly linked to the malignant progression of gastric tumor cells. (C) 2003 Wiley-Liss, Inc.