Microalterations of Inherently Unstable Genomic Regions in Rat Mammary Carcinomas as Revealed by Long Oligonucleotide Array-Based Comparative Genomic Hybridization
Microalterations of Inherently Unstable Genomic Regions in Rat Mammary Carcinomas as Revealed by Long Oligonucleotide Array-Based Comparative Genomic Hybridization
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DOI：
10.1158/0008-5472.can-08-4038
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发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Sugg, Sonia L.
中科院分区：
文献类型：
--
作者：
Adamovic, Tatjana;McAllister, Donna;Sugg, Sonia L.
由于使用不成对的参考DNA，正常基因组中拷贝数变异的存在对高分辨率癌症基因组分析研究中鉴定小的真正体细胞拷贝数变化提出了挑战。另一个问题是众所周知的淋巴细胞中免疫球蛋白和t细胞受体基因的重排（一种常用的参考），这可能会将研究人员误导到与肿瘤发生无关的位点。我们在这里展示了在归一化到配对乳腺后，致癌物质诱导的大鼠乳腺肿瘤样本中IgG重链V基因区域的真正增益，配对乳腺是一个没有淋巴细胞浸润的组织。我们进一步发现，包含IgG重链V基因的片段复制区域在乳腺肿瘤发生的近交系鼠易感（SS）和抗性（BN）之间存在拷贝数变异。我们的数据表明，当暴露于致癌物（7,12-二甲基苯[a]蒽）时，已经固有不稳定的基因组区域是在体细胞水平上进行额外结构重排（获得）的方便目标，这随后似乎有利于易感菌株乳腺中的肿瘤发展。因此，选择合适的参考DNA使我们能够确定免疫球蛋白基因作为在乳腺肿瘤发展中起作用的新癌症靶点。我们的结论是，在基于阵列的比较基因组杂交实验中，对照DNA的选择应该谨慎，来自混合脾脏（含有未成熟淋巴细胞，在动物研究中用作参考）或血液的DNA可能不是原发性肿瘤研究的理想对照。[癌症研究2009；69 (12): 5159 - 67)
The presence of copy number variants in normal genomes poses a challenge to identify small genuine somatic copy number changes in high-resolution cancer genome profiling studies due to the use of unpaired reference DNA. Another problem is the well-known rearrangements of immunoglobulin and T-cell receptor genes in lymphocytes (a commonly used reference), which may misdirect the researcher to a locus with no relevance in tumorigenesis. We here show real gains of the IgG heavy chain V gene region in carcinogen-induced rat mammary tumor samples after normalization to paired mammary gland, a tissue without lymphocyte infiltration. We further show that the segmental duplication region encompassing the IgG heavy chain V genes is a copy number variant between the susceptible (SS) and the resistant (BN) to mammary tumor development inbred rat strains. Our data suggest that the already inherently unstable genomic region is a convenient target for additional structural rearrangements (gains) at the somatic level when exposed to a carcinogen (7,12-dimethylbenz[a]anthracene), which subsequently seem to benefit tumor development in the mammary gland of the susceptible strain. Thus, the selection of an appropriate reference DNA enabled us to identify immunoglobulin genes as novel cancer targets playing a role in mammary tumor development. We conclude that control DNA in array-based comparative genomic hybridization experiments should be selected with care, and DNA from pooled spleen (contains immature lymphocytes and is used as reference in animal studies) or blood may not be the ideal control in the study of primary tumors. [Cancer Res 2009;69(12):5159-67]