Qiu Wanglong, Schönleben Frank, Li Xiaojun, Ho Daniel J, Close Lanny G, Manolidis Spiros, Bennett Boyce P, Su Gloria H
Department of Otolaryngology/Head and Neck Surgery, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Clin Cancer Res. 2006 Mar 1;12(5):1441-6. doi: 10.1158/1078-0432.CCR-05-2173.
Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic alpha (PIK3CA) gene in several human solid tumors. Although gene amplifications of PIK3CA have been reported in head and neck squamous cell carcinoma (HNSCC), small mutation of the gene has not been evaluated in HNSCC previously. In this study, we examined the mutation frequency of PIK3CA in HNSCC.
More than 75% of the somatic mutations of PIK3CA are clustered in the helical (exon 9) and kinase domains (exon 20). To investigate the possible role of PIK3CA in HNSCC tumorigenesis, exons 1, 4, 5, 6, 7, 9, and 20 of the gene were analyzed by direct genomic DNA sequencing in 38 HNSCC specimens.
We identified four missense mutations in the seven exons of PIK3CA from 38 HNSCC specimens (11%). Three of the four mutations (i.e., H1047R, E542K, and E545K) have been previously reported as hotspot mutations. The remaining novel mutation, Y343C, is identified at exon 4 nucleotide 1028 A --> G. Three of the four mutations were shown to be somatic, whereas the fourth mutation (H1047R) was identified in a cell line. Interestingly, three of the four mutations identified were in pharyngeal cancer samples.
These data provide evidence that oncogenic properties of PIK3CA contribute to the carcinogenesis of human head and neck cancers, especially in pharyngeal cancer. A specific kinase inhibitor to PIK3CA may potentially be an effective therapeutic reagent against HNSCC or pharyngeal cancer in particular.
近期研究报道了几种人类实体瘤中磷酸肌醇-3-激酶催化亚基α（PIK3CA）基因的体细胞突变高频发生。虽然头颈部鳞状细胞癌（HNSCC）中已有PIK3CA基因扩增的报道，但该基因的小突变此前尚未在HNSCC中进行评估。在本研究中，我们检测了HNSCC中PIK3CA的突变频率。
PIK3CA的体细胞突变超过75%聚集在螺旋结构域（外显子9）和激酶结构域（外显子20）。为研究PIK3CA在HNSCC肿瘤发生中的可能作用，通过直接基因组DNA测序分析了38例HNSCC标本中该基因的外显子1、4、5、6、7、9和20。
我们在38例HNSCC标本的PIK3CA的7个外显子中鉴定出4个错义突变（11%）。4个突变中的3个（即H1047R、E542K和E545K）此前已报道为热点突变。其余新突变Y343C在外显子4核苷酸1028处由A突变为G。4个突变中的3个显示为体细胞突变，而第4个突变（H1047R）在一个细胞系中被鉴定出。有趣的是，鉴定出的4个突变中有3个存在于咽癌样本中。
这些数据证明PIK3CA的致癌特性有助于人类头颈部癌，尤其是咽癌的发生。针对PIK3CA的特异性激酶抑制剂可能潜在地成为对抗HNSCC尤其是咽癌的有效治疗试剂。
