Persson F, Winnes M, Andrén Y, Wedell B, Dahlenfors R, Asp J, Mark J, Enlund F, Stenman G
Lundberg Laboratory for Cancer Research, Department of Pathology, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden.
Oncogene. 2008 May 8;27(21):3072-80. doi: 10.1038/sj.onc.1210961. Epub 2007 Dec 3.
We have previously identified a subgroup of pleomorphic salivary gland adenomas with ring chromosomes of uncertain derivation. Here, we have used spectral karyotyping (SKY), fluorescence in situ hybridization (FISH) and high-resolution oligonucleotide array-CGH to determine the origin and content of these rings and to identify genes disrupted as a result of ring formation. Of 16 tumors with rings, 11 were derived from chromosome 8, 3 from chromosome 5 and 1 each from chromosomes 1, 6 and 9. Array-CGH revealed that 10/11 r(8) consisted of amplification of a 19 Mb pericentromeric segment with recurrent breakpoints in FGFR1 in 8p12 and in PLAG1 in 8q12.1. Molecular analyses revealed that ring formation consistently generated novel FGFR1-PLAG1 gene fusions in which the 5'-part of FGFR1 is linked to the coding sequence of PLAG1. An alternative mechanism of PLAG1 activation was found in tumors with copy number gain of an intact PLAG1 gene. Rings derived from chromosomes 1, 5, 6 or 9 did not result in gene fusions, but rather resulted in losses indicative of the involvement of putative tumor suppressor genes on 8p, 5p, 5q and/or 6q. Our findings also reveal a novel mechanism by which FGFR1 contributes to oncogenesis and further illustrate the versatility of the FGFR1 and PLAG1 genes in tumorigenesis.
我们之前已鉴定出一组具有来源不明的环状染色体的多形性腺样瘤。在此，我们使用光谱核型分析（SKY）、荧光原位杂交（FISH）和高分辨率寡核苷酸阵列比较基因组杂交（array-CGH）来确定这些环状染色体的起源和内容，并鉴定因环状染色体形成而被破坏的基因。在16例有环状染色体的肿瘤中，11例来源于8号染色体，3例来源于5号染色体，1例分别来源于1号、6号和9号染色体。阵列比较基因组杂交显示，11个r(8)中有10个由一个19 Mb的着丝粒周围片段扩增组成，在8p12的FGFR1和8q12.1的PLAG1中有反复出现的断点。分子分析显示，环状染色体形成一致产生新的FGFR1-PLAG1基因融合，其中FGFR1的5'部分与PLAG1的编码序列相连。在完整PLAG1基因拷贝数增加的肿瘤中发现了PLAG1激活的另一种机制。来源于1号、5号、6号或9号染色体的环状染色体未导致基因融合，而是导致了缺失，提示8p、5p、5q和/或6q上可能的肿瘤抑制基因受累。我们的研究结果还揭示了FGFR1促进肿瘤发生的一种新机制，并进一步说明了FGFR1和PLAG1基因在肿瘤发生中的多功能性。
