Targets of genome copy number reduction in primary breast cancers identified by integrative genomics
Targets of genome copy number reduction in primary breast cancers identified by integrative genomics
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DOI：
10.1002/gcc.20411
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发表时间：
2007-03-01
影响因子：
3.7
通讯作者：
Tan, Patrick
中科院分区：
文献类型：
--
作者：
Chen, Wei;Salto-Tellez, Manuel;Tan, Patrick
在复发性非整倍体区域鉴定特异性癌基因和抑癌基因是肿瘤分子研究的主要挑战。使用寡核苷酸单核苷酸多态性和mRNA表达阵列，我们整合了基因组和转录信息，以确定和优先考虑候选癌症基因的区域增加和减少染色体拷贝数在一个队列的原发性乳腺癌。证实了这种方法的有效性，可以成功地重新鉴定乳腺癌中先前已知的拷贝数（CN）改变的几个区域。针对CN降低的区域，我们定义了18个候选基因的优先级列表，其中包括先前显示与乳腺癌或其他组织类型的癌症相关的ARPIN、FBNI和LZTSI，以及新基因如P29、MORF 4LI和TBCID 5。一个这样的基因，RUNX 3转录因子，被选择用于进一步研究。我们表明，RUNX 3以减少的CN与肿瘤基因组的其余部分成比例存在，并且RUNX 3 CN减少也可以在来自不同中心的乳腺癌系列中观察到。使用组织微阵列，我们在超过120个乳腺组织的独立队列中证明，RUNX 3蛋白在正常乳腺上皮中表达，但在脂肪和基质组织中不表达，并且在大多数乳腺癌中广泛下调（> 85%）。在体外，RUNX 3过表达在基质胶测定中抑制MDA-MB-231乳腺癌细胞的侵袭潜力。我们的研究结果证明了整合基因组方法在原发性肿瘤中识别新的潜在癌症相关基因的实用性。本文包含可在http：//www.example.com上获得的补充材料。www.interscience.wiley.com/jpages/1045-2257/suppmat (c)2006威利-利斯公司
The identification of specific oncogenes and tumor suppressor genes in regions of recurrent aneuploidy is a major challenge of molecular cancer research. Using both oligonucleotide single-nucleotide polymorphism and mRNA expression arrays, we integrated genomic and transcriptional information to identify and prioritize candidate cancer genes in regions of increased and decreased chromosomal copy number in a cohort of primary breast cancers. Confirming the validity of this approach, several regions of previously-known copy number (CN) alterations in breast cancer could be successfully reidentified. Focusing on regions of decreased CN, we defined a prioritized list of eighteen candidate genes, which included ARPIN, FBNI, and LZTSI, previously shown to be associated with cancers in breast or other tissue types, and novel genes such as P29, MORF4LI, and TBCID5. One such gene, the RUNX3 transcription factor, was selected for further study. We show that RUNX3 is present at reduced CNs in proportion to the rest of the tumor genome and that RUNX3 CN reductions can also be observed in a breast cancer series from a different center. Using tissue microarrays, we demonstrate in an independent cohort of over 120 breast tissues that RUNX3 protein is expressed in normal breast epithelium but not fat and stromal tissue, and widely down-regulated in the majority of breast cancers (> 85%). In vitro, RUNX3 overexpression suppressed the invasive potential of MDA-MB-231 breast cancer cells in a matrigel assay. Our results demonstrate the utility of integrative genomic approaches to identify novel potential cancer-related genes in primary tumors. This article contains Supplementary Material available at http:// www.interscience.wiley.com/jpages/1045-2257/suppmat. (c) 2006 Wiley-Liss, Inc.