Research Article: CRX Is a Diagnostic Marker of Retinal and Pineal Lineage Tumors

Date Published: November 20, 2009

Publisher: Public Library of Science

Author(s): Sandro Santagata, Cecile L. Maire, Ahmed Idbaih, Lars Geffers, Mick Correll, Kristina Holton, John Quackenbush, Keith L. Ligon, Patrick Callaerts.

Abstract: 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.

Partial Text: Pineal parenchymal tumors predominantly affect children, and account for approximately one-quarter of all neoplasms of the pineal region [1]. These tumors exhibit a spectrum of clinical aggressiveness that include pineocytomas, which are low-grade well-differentiated and indolent tumors often with large pineocytomatous rosettes; pineoblastomas, which are high-grade poorly-differentiated aggressive embryonal tumors with dense sheets of poorly differentiated small cells and pineal parenchymal tumors of intermediate differentiation (PPTID), which have an intermediate grade and prognosis[2]–[7]. The appropriate pathologic classification and grading of tumors of the pineal region is essential for determining clinical management and prognosis[8], however, the diagnostic evaluation is often difficult due to the inherently small size of the biopsies for diagnosis and the wide array of tumor types that can involve the pineal gland[3], [9]. The most common tumors entering the differential diagnosis are CNS germ cell tumors, primitive neuroectodermal tumors, gliomas, atypical teratoid/rhabdoid tumors and anaplastic ependymoma[2], [6], [10]. However, specific markers which can positively identify all pineal lineage tumors are generally lacking in clinical practice. In addition, research into the biology and treatment of these neoplasms has been severely hindered by the rare nature of the tumors, the lack of primary tissue available for study, and the scarcity of relevant cell lines or mouse models of the disease. Each of these research areas would greatly benefit from the discovery of reliable markers of the disease.

Advances in the study of the normal pineal and pineal region tumors has been limited in part due to their very infrequent occurrence, with tumors of the pineal region accounting for less than 0.1% of all intracranial tumors. Here we hypothesized that lineage restricted transcription factors for retino-pineal progenitors might represent useful diagnostic and investigational tools as has been demonstrated in other cancers[28], [29], [50], [51]. The molecular-genetic similarity between the retina and pineal and the remarkably restricted expression pattern of Crx mRNA suggested a distinct opportunity for employing Crx as a candidate biomarker. Our studies of RNA ISH in whole embryos and brain confirm the remarkable lineage restiction of this gene across the whole mouse embryo. Furthermore, our studies in human systems using IHC and expression profiling data validate that such lineage restriction is highly preserved in humans as well. Given that CRX protein expression had not been previously as well studied, we find that the RNA and protein expression are highly conserved with no significant differences detected in our study.



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