Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas
Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas
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DOI：
10.1038/ng771
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发表时间：
2001-12-01
期刊：
影响因子：
30.8
通讯作者：
Gray, JW
中科院分区：
文献类型：
--
作者：
Hodgson, G;Hager, JH;Gray, JW
在大鼠胰岛素II启动子（RIP）的转录控制下表达SV 40 T抗原（Tag）的转基因小鼠的胰岛中发展的癌通过与人肿瘤进展的方面相似的充分表征的阶段进展，包括增生性生长、增加的血管生成和减少的细胞增殖。后两个阶段与复发性杂合性丢失（洛）（2）和9号染色体（LOH 9）和16号染色体（LOH 16）上基因组拷贝数减少（3）有关，我们认为这些表型是由畸变引起的。早期的分析将LOH 9定位于约3 Mb，LOH 16定位于约30 Mb（均与人3q 21-q25同线），但受到低通量和缺乏信息多态性标记的限制。在这里，我们表明，比较基因组杂交到DNA微阵列（阵列CGH）（4-7）克服了这些限制，允许有效的，全基因组分析的相对基因组拷贝数。这些实验中使用的CGH阵列携带以2-20-MB间隔分布在小鼠基因组中的BAC，并且在感兴趣的区域中以更高的密度分布。使用阵列CGH，我们进一步缩小了LOH 9和LOH 16的基因座，并在染色体6、8和14上定义了新的或以前未被重视的拷贝数减少的复发区域（与人类染色体12 p11-p13、16q24.3和13 q11-q32同线，在2号和4号染色体上（分别与人类染色体20q13.2和1 p32-p36同线），拷贝数增加的区域。我们对与这些区域同线的人类基因组序列的分析表明，CYP 24、PFDN 4、STMN 1、CDKN 1B、PPP 2 R3和FSTL 1是候选癌基因或肿瘤抑制基因。我们还表明，辐射和遗传背景的影响频谱畸变存在于这些肿瘤。
Carcinomas that develop in the pancreatic islets of transgenic mice expressing the SV40 T-antigens (Tag) under transcriptional control of the rat insulin II promoter (RIP) progress through well-characterized stages that are similar to aspects of human tumor progression, including hyperplastic growth, increased angiogenesis and reduced apoptosis'. The latter two stages have been associated with recurrent loss of heterozygosity (LOH)(2) and reduced genome copy number(3) on chromosomes 9 (LOH9) and 16 (LOH16), aberrations which we believe contribute to these phenotypes. Earlier analyses localized LOH9 to approximately 3 Mb and LOH16 to approximately 30 Mb (both syntenic with human 3q21-q25) but were limited by low throughput and a lack of informative polymorphic markers. Here we show that comparative genomic hybridization to DNA microarrays (array CGH)(4-7) overcomes these limitations by allowing efficient, genome-wide analyses of relative genome copy number. The CGH arrays used in these experiments carried BACs distributed at 2-20-MB intervals across the mouse genome and at higher density in regions of interest. Using array CGH, we further narrowed the loci for LOH9 and LOH16 and defined new or previously unappreciated recurrent regions of copy-number decrease on chromosomes 6, 8 and 14 (syntenic with human chromosomes 12p11-p13, 16q24.3 and 13q11-q32, respectively) and regions of copy-number increase on chromosomes 2 and 4 (syntenic to human chromosomes 20q13.2 and 1p32-p36, respectively). Our analyses of human genome sequences syntenic to these regions suggest that CYP24, PFDN4, STMN1, CDKN1B, PPP2R3 and FSTL1 are candidate oncogenes or tumor-suppressor genes. We also show that irradiation and genetic background influence the spectrum of aberrations present in these tumors.