Genome-based identification of cancer genes by proviral tagging in mouse retrovirus-induced T-cell lymphornas
Genome-based identification of cancer genes by proviral tagging in mouse retrovirus-induced T-cell lymphornas
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DOI：
10.1128/jvi.77.3.2056-2062.2003
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发表时间：
2003-02-01
影响因子：
5.4
通讯作者：
Lenz, J
中科院分区：
文献类型：
--
作者：
Kim, R;Trubetskoy, A;Lenz, J
肿瘤诱导基因的鉴定是阐明癌症分子机制的驱动力。许多逆转录病毒通过插入细胞癌基因附近的病毒DNA诱导肿瘤，导致编码蛋白的表达和/或结构改变。小鼠基因组序列的可用性现在允许分析小鼠肿瘤中逆转录病毒的共同整合位点，作为鉴定大量候选癌症基因的遗传筛选。通过定位逆转录病毒SL3-3诱导的t细胞淋巴瘤的逆转录病毒-宿主连接片段序列，鉴定了19个靶基因。候选癌症基因包括转录因子（Fos、Gfi1、Lef1、Myb、Myc、Runx3和Sox3）、所有三种D细胞周期蛋白、Ras信号通路组分（Rras2/TC21和Rasgrp1）和Cmkbr7/CCR7。最常见的目标是Rras2。距离转录部分57 kb的插入与Rras2转录显著增加相关，没有检测到编码序列突变，包括那些通常与Ras激活有关的突变。这些研究证明了基于基因组的逆转录病毒插入位点分析在发现癌症基因方面的力量，确定了几个值得研究的在人类癌症中起作用的新基因，并揭示了这些基因在淋巴瘤发生中的作用途径。他们还提供了强有力的遗传证据，证明未突变的Rras2过表达有助于肿瘤的发生，因此，如果它在人类肿瘤中不适当表达，也可能有助于肿瘤的发生。
The identification of tumor-inducing genes is a driving force for elucidating the molecular mechanisms underlying cancer. Many retroviruses induce tumors by insertion of viral DNA adjacent to cellular oncogenes, resulting in altered expression and/or structure of the encoded proteins. The availability of the mouse genome sequence now allows analysis of retroviral common integration sites in murine tumors to be used as a genetic screen for identification of large numbers of candidate cancer genes. By positioning the sequences of inverse PCR-amplified, virus-host junction fragments within the mouse genome, 19 target genes were identified in T-cell lymphomas induced by the retrovirus SL3-3. The candidate cancer genes included transcription factors (Fos, Gfi1, Lef1, Myb, Myc, Runx3, and Sox3), all three D cyclins, Ras signaling pathway components (Rras2/TC21 and Rasgrp1), and Cmkbr7/CCR7. The most frequent target was Rras2. Insertions as far as 57 kb away from the transcribed portion were associated with substantially increased transcription of Rras2, and no coding sequence mutations, including those typically involved in Ras activation, were detected. These studies demonstrate the power of genome-based analysis of retroviral insertion sites for cancer gene discovery, identify several new genes worth examining for a role in human cancer, and implicate the pathways in which those genes act in lymphomagenesis. They also provide strong genetic evidence that overexpression of unmutated Rras2 contributes to tumorigenesis, thus suggesting that it may also do so if it is inappropriately expressed in human tumors.