Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer.
Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer.
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DOI：
10.1038/onc.2011.554
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发表时间：
2012-08-30
期刊：
影响因子：
8
通讯作者：
Xu, J.
中科院分区：
文献类型：
--
作者：
Liu, W.;Lindberg, J.;Sui, G.;Luo, J.;Egevad, L.;Li, T.;Xie, C.;Wan, M.;Kim, S-T;Wang, Z.;Turner, A. R.;Zhang, Z.;Feng, J.;Yan, Y.;Sun, J.;Bova, G. S.;Ewing, C. M.;Yan, G.;Gielzak, M.;Cramer, S. D.;Vessella, R. L.;Zheng, S. L.;Gronberg, H.;Isaacs, W. B.;Xu, J.
目前迫切需要更清楚地定义推动前列腺癌（PCa）发展和进展的分子决定因素。在肿瘤基因组中定位复发性体细胞缺失，特别是纯合缺失（HOD）的努力，为寻找致癌基因提供了重要的位置信息。使用高分辨率单核苷酸多态性阵列分析来自两个独立队列的244例患者和22例PCa异种移植物的肿瘤中的HOD，在此我们报告了CHD1的鉴定，CHD1是一种染色质重塑剂，是PCa中最常见的同源性缺失基因之一，在这方面仅次于PTEN。在CHD1中观察到的HOD，包括仅影响CHD1内部外显子的缺失，被发现完全消除PCa异种移植物中该基因的mRNA表达。临床标本中这种染色质重塑的丢失与额外染色体缺失的数量增加显著相关，包括半合子和纯合子，特别是在2q、5q和6q上。结合在CHD1小发夹RNA稳定转染的HEK293细胞中观察到的缺失，这些数据表明存在因果关系。Chd 1在小鼠前列腺上皮细胞中的下调引起了显着的形态学变化，表明增加的侵袭性，但没有导致转化。这些发现表明CHD1的新作用，共同表明，不同的CHD1相关的基因组结构的改变在PCa的发展过程中演变，并需要PCa的发展。
A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.
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影响因子：
30.8
作者：
Carver, Brett S.;Tran, Jennifer;Gopalan, Anuradha;Chen, Zhenbang;Shaikh, Safa;Carracedo, Arkaitz;Alimonti, Andrea;Nardella, Caterina;Varmeh, Shohreh;Scardino, Peter T.;Cordon-Cardo, Carlos;Gerald, William;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Gaspar-Maia A;Alajem A;Polesso F;Sridharan R;Mason MJ;Heidersbach A;Ramalho-Santos J;McManus MT;Plath K;Meshorer E;Ramalho-Santos M
通讯作者：
Ramalho-Santos M
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.