High-Resolution Genomic Profiling of Adenomas and Carcinomas of the Salivary Glands Reveals Amplification, Rearrangement, and Fusion of HMGA2
High-Resolution Genomic Profiling of Adenomas and Carcinomas of the Salivary Glands Reveals Amplification, Rearrangement, and Fusion of HMGA2
复制标题
DOI：
10.1002/gcc.20619
复制
发表时间：
2009-01-01
影响因子：
3.7
通讯作者：
Stenman, Goran
中科院分区：
文献类型：
--
作者：
Persson, Fredrik;Andren, Ywonne;Stenman, Goran
癌前多形性腺瘤（Ca-ex-PA）是一种发生在良性涎腺多形性腺瘤（PA）内的上皮恶性肿瘤。在这里，我们使用全基因组、高分辨率阵列- cgh和荧光原位杂交来鉴定在双min染色体和PA和Ca-ex-RA的均匀染色区域扩增的基因，并鉴定这些肿瘤类型的其他基因组失衡特征。分析的16个肿瘤中有10个显示了一个30 kb的最小公共区域的扩增/增益，该区域由HMGA2的5'部分组成（编码三个dna结合域）。在9个肿瘤中发现MDM2的共扩增。5例肿瘤存在隐性HMGA2-WIF1基因融合，4例肿瘤存在融合癌基因扩增。对12q中8个扩增候选基因的表达分析显示，HMGA2和MDM2扩增/重排的肿瘤的表达水平明显高于未扩增的肿瘤。对HMGA2单个外显子的分析显示，在10个HMGA2激活的肿瘤中，有9个肿瘤的外显子3-5的表达比外显子1-2的表达明显降低，表明HMGA2基因融合和重排在扩增的肿瘤中很常见。此外，还发现了1q11-q32.1、2p16.1-p12、8q12.1、8q22-24.1和20的反复扩增/增益，以及1p21.3-p21.1、5q23.2-q31.2、8p、10q21.3和15q11.2的反复扩增/增益。总之，我们的研究结果确定HMGA2和MDM2是PA和ca -前PA的扩增靶点，并提示12q基因的扩增（特别是MDM2）， 5q23.2-q31.2的缺失，8q12.1 （PLAG1）和8q22.1-q24.1 （MYC）的增加，以及ERBB2的扩增可能是良性PA恶性转化的重要因素。(C) 2008 Wiley-Liss, Inc。
Carcinoma ex pleomorphic adenoma (Ca-ex-PA) is an epithelial malignancy developing within a benign salivary gland pleomorphic adenoma (PA). Here we have used genome-wide, high-resolution array-CGH, and fluorescence in situ hybridization to identify genes amplified in double min chromosomes and homogeneously staining regions in PA and Ca-ex-RA and to identify additional genomic imbalances characteristic of these tumor types. Ten of the 16 tumors analyzed showed amplification/gain of a 30-kb minimal common region, consisting of the 5'-part of HMGA2 (encoding the three DNA-binding domains). Coamplification of MDM2 was found in nine tumors. Five tumors had cryptic HMGA2-WIF1 gene fusions with amplification of the fusion oncogene in four tumors. Expression analysis of eight amplified candidate genes in 12q revealed that tumors with amplification/rearrangement of HMGA2 and MDM2 had significantly higher expression levels when compared with tumors without amplification. Analysis of individual HMGA2 exons showed that the expression of exons 3-5 were substantially reduced when compared with exons 1-2 in 9 of 10 tumors with HMGA2 activation, indicating that gene fusions and rearrangements of HMGA2 are common in tumors with amplification. In addition, recurrent amplifications/gains of 1q11-q32.1, 2p16.1-p12, 8q12.1, 8q22-24.1, and 20, and losses of 1p21.3-p21.1, 5q23.2-q31.2, 8p, 10q21.3, and 15q11.2 were identified. Collectively, our results identify HMGA2 and MDM2 as amplification targets in PA and Ca-ex-PA and suggest that amplification of 12q genes (in particular MDM2), deletions of 5q23.2-q31.2, gains of 8q12.1 (PLAG1) and 8q22.1-q24.1 (MYC), and amplification of ERBB2 may be of importance for malignant transformation of benign PA. (C) 2008 Wiley-Liss, Inc.