Hui Angela Bik-Yu, Or Yvonne Yan-Yan, Takano Hirokuni, Tsang Raymond King-Yin, To Ka-Fai, Guan Xin-Yuen, Sham Jonathan Shun-Tong, Hung Katherine Wing-Ki, Lam Cleo Nga-Yee, van Hasselt Charles Andrew, Kuo Wen-Lin, Gray Joe W, Huang Dolly P, Lo Kwok-Wai
Departments of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR.
Cancer Res. 2005 Sep 15;65(18):8125-33. doi: 10.1158/0008-5472.CAN-05-0648.
Nasopharyngeal carcinoma is highly prevalent in Southern China and Southeast Asia. To unveil the molecular basis of this endemic disease, high-resolution comparative genomic hybridization arrays were used for systematic investigation of genomic abnormalities in 26 nasopharyngeal carcinoma samples. A comprehensive picture of genetic lesions associated with tumorigenesis of nasopharyngeal carcinoma was generated. Consistent chromosomal gains were frequently found on 1q, 3q, 8q, 11q, 12p, and 12q. High incidences of nonrandom losses were identified on chromosomes 3p, 9p, 11q, 14q, and 16q. In addition to previously characterized regions, we have identified several novel minimal regions of gains, including 3q27.3-28, 8q21-24, 11q13.1-13.3, and 12q13, which may harbor candidate nasopharyngeal carcinoma-associated oncogenes. In this study, gain of 11q13.1-13.3 was the most frequently detected chromosomal aberration and a 5.3-Mb amplicon was delineated at this region. Within this 11q13 amplicon, concordant amplification and overexpression of cyclin D1 (CCND1) oncogene was found in nasopharyngeal carcinoma cell lines, xenografts, and primary tumors. Knockdown of cyclin D1 by small interfering RNA in nasopharyngeal carcinoma cell lines led to significant decrease of cell proliferation. The findings suggest that cyclin D1 is a target oncogene at 11q13 in nasopharyngeal carcinoma and its activation plays a significant role in nasopharyngeal carcinoma tumorigenesis.
鼻咽癌在中国南方和东南亚地区高度流行。为了揭示这种地方病的分子基础，我们使用高分辨率比较基因组杂交阵列对26例鼻咽癌样本的基因组异常进行了系统研究。由此生成了一幅与鼻咽癌发生相关的基因损伤的全面图谱。在1q、3q、8q、11q、12p和12q上经常发现一致的染色体增加。在3p、9p、11q、14q和16q染色体上发现了非随机缺失的高发生率。除了先前已鉴定的区域外，我们还鉴定了几个新的最小增加区域，包括3q27.3 - 28、8q21 - 24、11q13.1 - 13.3和12q13，这些区域可能含有与鼻咽癌相关的候选致癌基因。在本研究中，11q13.1 - 13.3的增加是最常检测到的染色体畸变，并且在该区域划定了一个5.3兆碱基的扩增子。在这个11q13扩增子内，在鼻咽癌细胞系、异种移植瘤和原发性肿瘤中发现细胞周期蛋白D1（CCND1）致癌基因的一致扩增和过表达。在鼻咽癌细胞系中通过小干扰RNA敲低细胞周期蛋白D1导致细胞增殖显著下降。这些发现表明，细胞周期蛋白D1是鼻咽癌11q13处的一个靶致癌基因，其激活在鼻咽癌发生中起重要作用。
