An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer
An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer
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DOI：
10.1038/onc.2011.386
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发表时间：
2012-04-01
期刊：
影响因子：
8
通讯作者：
Basik, M.
中科院分区：
文献类型：
--
作者：
Mamo, A.;Cavallone, L.;Basik, M.
肿瘤抑制基因（TSGs）被经典地定义为在肿瘤细胞中功能丧失有助于形成和/或维持肿瘤表型的基因。含有无义突变的tsg可能由于无义介导的RNA衰变（NMD）而无法表达。为了在5种乳腺癌细胞系中鉴定候选tsg，我们将NMD过程的抑制与高密度单核苷酸多态性阵列分析相结合，该过程可以清除含有无义突变的转录本，以区分等位基因含量。我们在T47D乳腺癌细胞系中发现ARID1A是NMD的靶标，可能是由于外显子9的突变，该突变在Q944位置引入了一个过早停止密码子。ARID1A编码酵母SWI1的人类同源物，SWI1是hSWI/SNF复合体的一个组成部分，hSWI/SNF复合体是一种依赖于atp的染色质重塑多亚基酶。尽管我们没有在11个乳腺肿瘤中发现任何体细胞突变，这些突变显示ARID1A附近1p36位点的DNA拷贝数丢失，但我们发现，在两个独立的200多例人类乳腺癌病例中，ARID1A RNA或核蛋白的低表达与更具侵袭性的乳腺癌表型（如高肿瘤分级）相关。我们还发现，低ARID1A核表达在乳腺肿瘤进展的后期变得更加普遍。最后，我们发现ARID1A在T47D细胞系中的重新表达对软琼脂中的集落形成有显著的抑制作用。这些结果提示ARID1A可能是乳腺癌的候选TSG。中国癌症杂志（2012）31,2090-2100；doi: 10.1038 / onc.2011.386;2011年9月5日在线发布
Tumor-suppressor genes (TSGs) have been classically defined as genes whose loss of function in tumor cells contributes to the formation and/or maintenance of the tumor phenotype. TSGs containing nonsense mutations may not be expressed because of nonsense-mediated RNA decay (NMD). We combined inhibition of the NMD process, which clears transcripts that contain nonsense mutations, with the application of high-density single-nucleotide polymorphism arrays analysis to discriminate allelic content in order to identify candidate TSGs in five breast cancer cell lines. We identified ARID1A as a target of NMD in the T47D breast cancer cell line, likely as a consequence of a mutation in exon-9, which introduces a premature stop codon at position Q944. ARID1A encodes a human homolog of yeast SWI1, which is an integral member of the hSWI/SNF complex, an ATP-dependent, chromatin-remodeling, multiple-subunit enzyme. Although we did not find any somatic mutations in 11 breast tumors, which show DNA copy-number loss at the 1p36 locus adjacent to ARID1A, we show that low ARID1A RNA or nuclear protein expression is associated with more aggressive breast cancer phenotypes, such as high tumor grade, in two independent cohorts of over 200 human breast cancer cases each. We also found that low ARID1A nuclear expression becomes more prevalent during the later stages of breast tumor progression. Finally, we found that ARID1A re-expression in the T47D cell line results in significant inhibition of colony formation in soft agar. These results suggest that ARID1A may be a candidate TSG in breast cancer. Oncogene (2012) 31, 2090-2100; doi: 10.1038/onc.2011.386; published online 5 September 2011