Expression ratio of CCND1 to CDKN2A mRNA predicts RB1 status of cultured cancer cell lines and clinical tumor samples.
Expression ratio of CCND1 to CDKN2A mRNA predicts RB1 status of cultured cancer cell lines and clinical tumor samples.
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DOI：
10.1186/1476-4598-10-31
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发表时间：
2011-03-29
期刊：
影响因子：
37.3
通讯作者：
Kotani H
中科院分区：
文献类型：
--
作者：
Mizuarai S;Machida T;Kobayashi T;Komatani H;Itadani H;Kotani H
视网膜母细胞瘤产物(RB1)在各种类型的肿瘤中经常因突变、缺失或与病毒癌蛋白结合而失活而被解除调控。RB1功能缺失被认为是区分癌细胞和正常细胞的标志之一。许多研究人员正试图开发出对RB1阴性肿瘤更有效的抗肿瘤药物。然而，为了识别RB1阴性的癌症患者，必须开发预测性生物标记物来区分RB1阳性和阴性肿瘤。对由16个RB1阳性和14个RB1阴性的癌细胞组成的30个癌细胞株的表达谱进行了分析，以寻找两组之间差异表达的基因，从而确定了194个基因的RB1特征。其中包括关键的RB1途径组分CDKN2A和CCND1。我们发现，CCND1和CDKN2A的表达比例的微阵列数据清楚地区分了30个细胞株的RB1状态。通过RT-PCR检测额外细胞系中CCND1/CDKN2AmRNA的表达比率，可以准确地预测RB1的状态(12/12细胞系)。CCND1/CDKN2A在体内移植瘤中的表达与RB1状态有关。最后，临床样本的CCND1/CDKN2A检测显示，已知的RB1基因高发的子宫颈癌和小细胞肺癌的RB1基因转阴率为100%，而子宫内膜癌或胃癌的转阴率为5%-22%。所有临床正常组织均为100%RB1阳性。我们在此报道，CCND1/CDKN2AmRNA表达比率可以预测体外细胞系、体内异种移植瘤和临床肿瘤标本的RB1状态。鉴于CCND1/CDKN2A表达分析的高预测准确性和定量性质，该分析可用于对RB1阳性或阴性肿瘤优先使用抗肿瘤药物的患者进行分层。
The retinoblastoma product (RB1) is frequently deregulated in various types of tumors by mutation, deletion, or inactivation through association with viral oncoproteins. The functional loss of RB1 is recognized to be one of the hallmarks that differentiate cancer cells from normal cells. Many researchers are attempting to develop anti-tumor agents that are preferentially effective against RB1-negative tumors. However, to identify patients with RB1-negative cancers, it is imperative to develop predictive biomarkers to classify RB1-positive and -negative tumors. Expression profiling of 30 cancer cell lines composed of 16 RB1-positive and 14 RB1-negative cancers was performed to find genes that are differentially expressed between the two groups, resulting in the identification of an RB1 signature with 194 genes. Among them, critical RB1 pathway components CDKN2A and CCND1 were included. We found that microarray data of the expression ratio of CCND1 and CDKN2A clearly distinguished the RB1 status of 30 cells lines. Measurement of the CCND1/CDKN2A mRNA expression ratio in additional cell lines by RT-PCR accurately predicted RB1 status (12/12 cells lines). The expression of CCND1/CDKN2A also correlated with RB1 status in xenograft tumors in vivo. Lastly, a CCND1/CDKN2A assay with clinical samples showed that uterine cervical and small cell lung cancers known to have a high prevalence of RB1-decifiency were predicted to be 100% RB1-negative, while uterine endometrial or gastric cancers were predicted to be 5-22% negative. All clinically normal tissues were 100% RB1-positive. We report here that the CCND1/CDKN2A mRNA expression ratio predicts the RB1 status of cell lines in vitro and xenograft tumors and clinical tumor samples in vivo. Given the high predictive accuracy and quantitative nature of the CCND1/CDKN2A expression assay, the assay could be utilized to stratify patients for anti-tumor agents with preferential effects on either RB1-positive or -negative tumors.
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