Abstract
BackgroundThe 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.ResultsExpression 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.ConclusionsWe 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.
Highlights
The retinoblastoma product (RB1) is frequently deregulated in various types of tumors by mutation, deletion, or inactivation through association with viral oncoproteins
We found that the expression ratio of CCND1 to CDKN2A clearly classified RB1-positive and -negative cancer lines, the predictive accuracy of which was superior to that of individual CDKN2A or CCND1, respectively
We found that uterine cervical and small cell lung cancers were predicted to be RB-negative at high prevalence, while most uterine endometrial and stomach cancers were predicted to be RB1-positive by the CCND1/CDKN2A assay
Summary
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. The activity of RB1 is mainly regulated by the upstream CDKN2A/CCND1 pathway [3,4,5]. Anti-proliferative stresses including DNA damage, therapeutic agents, and anti-mitogens increase the expression of CDKN2A followed by the dissociation of CDK4 or CDK6/CCND1 complexes. The RB1 loss is caused by several molecular events such as point mutations, deletion, or inactivation through associating viral proteins [19]. Accumulating evidence has shown that hypermethylation in the promoter region of CDKN2A or overexpression of CCND1, which results in RB1 dysfunction, frequently occurs in various types of cancers [11]. Deregulation in the RB1 pathway is recognized to be a hallmark of tumorigenesis
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