Dataset Information

CRX is a diagnostic marker of retinal and pineal lineage tumors.

ABSTRACT:

Background

CRX is a homeobox transcription factor whose expression and function is critical to maintain retinal and pineal lineage cells and their progenitors. To determine the biologic and diagnostic potential of CRX in human tumors of the retina and pineal, we examined its expression in multiple settings.

Methodology/principal findings

Using situ hybridization and immunohistochemistry we show that Crx RNA and protein expression are exquisitely lineage restricted to retinal and pineal cells during normal mouse and human development. Gene expression profiling analysis of a wide range of human cancers and cancer cell lines also supports that CRX RNA is highly lineage restricted in cancer. Immunohistochemical analysis of 22 retinoblastomas and 13 pineal parenchymal tumors demonstrated strong expression of CRX in over 95% of these tumors. Importantly, CRX was not detected in the majority of tumors considered in the differential diagnosis of pineal region tumors (n = 78). The notable exception was medulloblastoma, 40% of which exhibited CRX expression in a heterogeneous pattern readily distinguished from that seen in retino-pineal tumors.

Conclusions/significance

These findings describe new potential roles for CRX in human cancers and highlight the general utility of lineage restricted transcription factors in cancer biology. They also identify CRX as a sensitive and specific clinical marker and a potential lineage dependent therapeutic target in retinoblastoma and pineoblastoma.

SUBMITTER: Santagata S

PROVIDER: S-EPMC2775954 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.

Project description:The cone-rod homeobox gene (Crx) encodes Crx, a transcription factor selectively expressed in two cell types, retinal photoreceptors and the melatonin secreting pinealocytes of the pineal gland. In this report the role of Crx in regulating gene expression in the mammalian pineal gland was extended using Affymetrix GeneChip technology. Deletion of Crx results in broad modulation of the mouse pineal transcriptome, including a >2-fold downregulation of 543 genes and a >2-fold upregulation of 745 genes. In addition to Crx, there was a >10-fold downregulation of 13 other genes. Of special interest was the discovery of a link between Crx and the homeobox gene Hoxc4, which was upregulated ~20-fold in the Crx-/- pineal gland. Analysis of night and day expression of genes indicated that a set of 51 genes exhibited differential expression in control animals. Of these genes, only eight were also differentially expressed in Crx-/- animals. This group included Aanat, which encodes the enzyme that controls the daily rhythm in melatonin synthesis in the vertebrate pineal gland. Accordingly, Crx appears to be essential for the 24-hour rhythmic component of expression of some genes in the pineal gland. In the Crx-/- mouse pineal gland, 41 genes exhibited differential night/day expression that was not seen in control animals, suggesting that Crx may function to modulate rhythmic expression of these genes as well. Together, the results of this investigation indicate that Crx broadly modulates the pineal transcriptome, perhaps in part through suppressive effects on expression of the homeobox gene Hoxc4. Pineal glands from control (129sv) mice and Crx-/- mice were collected at ZT6 and ZT20 for RNA extraction and hybridization on Affymetrix mouse 430_2 chip. Each condition were performed as triplicats. SUPPLEMENTARY FILES: The GCOS signal intensity data were analyzed using ChipInspector (Genomatix) version 2.1. FDR= 0, p-value <0.05, cut off=1, region size = 300 bp and 4 and 5 significant probes. Log(2) fold change independently of time of day. Up regulated genes: genes which are up regulated in Crx-/- compared to the control; down regulated genes: genes which are down regulated in Crx-/- compared to the control.