Comparative oncogenomic analysis of copy number alterations in human and zebrafish tumors enables cancer driver discovery.
Comparative oncogenomic analysis of copy number alterations in human and zebrafish tumors enables cancer driver discovery.
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DOI：
10.1371/journal.pgen.1003734
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发表时间：
2013-08
期刊：
影响因子：
4.5
通讯作者：
Lees JA
中科院分区：
文献类型：
--
作者：
Zhang G;Hoersch S;Amsterdam A;Whittaker CA;Beert E;Catchen JM;Farrington S;Postlethwait JH;Legius E;Hopkins N;Lees JA
识别癌症驱动因素是当前癌症研究的主要目标。在大的染色体事件中寻找驱动基因是特别具有挑战性的，因为这种改变包括许多基因。以前，我们证明了斑马鱼恶性外周神经鞘瘤（MPNSTs）是高度非整倍体，很像人类肿瘤。在这项研究中，我们通过大规模平行测序检查了147条斑马鱼MPNST，并确定了大拷贝数改变和局灶性拷贝数改变（CNA）。鉴于鱼类和哺乳动物之间的保守同线性程度较低，我们推断，对鱼类和人类MPNST的CNA进行比较分析，将能够消除大部分乘客突变，特别是在大型CNA上。我们建立了一个人类和斑马鱼之间的同源基因列表，其中包括大约三分之二的人类蛋白质编码基因。对于在人类MPNST CNA中发现的这些基因的子集，只有四分之一的直系同源物在斑马鱼中共同获得或共同丢失，大大缩小了局灶性和大型CNA的候选癌症驱动因素的列表。我们的结论是，斑马鱼-人类比较分析代表了一个强大的，广泛适用的工具，以丰富进化保守的癌症驱动程序。癌症本质上是一种遗传性疾病，由一系列遗传变化引起，包括点突变和染色体数目异常。后者导致许多基因的拷贝数改变。虽然在给定的肿瘤中通常有数千个这样的遗传变化，但只有一小部分可能导致癌症的发展。主要挑战之一是区分这些癌症“驱动”基因与不导致癌症表型的“乘客”突变。特别是，识别在肿瘤中经常获得或丢失的整个染色体上的驱动基因仍然是一个棘手的问题，因为这些改变包含如此多的基因。我们证明，由于基因的染色体位置是高度混乱的斑马鱼和人类之间，乘客基因的数量可以显着减少，通过比较在斑马鱼和人类肿瘤中发现的拷贝数改变的基因。因此，我们的方法大大缩小了候选癌症驱动因素的范围，并可以加速发现新的癌症驱动因素和途径，为未来的靶向治疗和个性化医疗提供信息。
The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given the low degree of conserved synteny between fish and mammals, we reasoned that comparative analyses of CNAs from fish versus human MPNSTs would enable elimination of a large proportion of passenger mutations, especially on large CNAs. We established a list of orthologous genes between human and zebrafish, which includes approximately two-thirds of human protein-coding genes. For the subset of these genes found in human MPNST CNAs, only one quarter of their orthologues were co-gained or co-lost in zebrafish, dramatically narrowing the list of candidate cancer drivers for both focal and large CNAs. We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers. Cancer is essentially a genetic disease, caused by serial genetic changes including point mutations and chromosome number abnormalities. The latter leads to copy number alterations of many genes. While there are usually thousands of these genetic changes in a given tumor, only a small fraction likely contribute to cancer development. One of the major challenges is to distinguish these cancer “driver” genes from “passenger” mutations that do not contribute to the cancer phenotype. In particular, identifying the driver genes on entire chromosomes that are frequently gained or lost in tumors remains a recalcitrant problem as these alterations contain so many genes. We demonstrate that, because the chromosomal location of genes is highly scrambled between zebrafish and human, the number of passenger genes can be dramatically reduced by comparing the genes in copy number alterations found in zebrafish and human tumors. Thus, our approach dramatically narrows down the list of candidate cancer drivers, and can accelerate discovery of novel cancer drivers and pathways that could inform future targeted therapy and personalized medicine.
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影响因子：
5.7
作者：
Chai, Guolin;Liu, Ning;Yu, Xijie
通讯作者：
Yu, Xijie
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0710052104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Beroukhim, Rameen;Getz, Gad;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
3.7
作者：
Beert, Eline;Brems, Hilde;Legius, Eric
通讯作者：
Legius, Eric
DOI：
10.1158/1078-0432.ccr-11-2049
发表时间：
2011-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bakhoum SF;Danilova OV;Kaur P;Levy NB;Compton DA
通讯作者：
Compton DA