Association of Cone-Rod Homeobox Transcription Factor Messenger RNA With Pediatric Metastatic Retinoblastoma.

Abstract

IMPORTANCE:

Disseminated retinoblastoma is usually fatal. Identification of small amounts (minimal dissemination [MD]) of tumor cells in extraocular sites might be a tool for designing appropriate treatments.

OBJECTIVE:

To test cone-rod homeobox (CRX) transcription factor as a lineage-specific molecular marker for metastatic retinoblastoma and for evaluation of MD.

DESIGN, SETTING, AND PARTICIPANTS:

In a prospective cohort design study, we evaluated CRX messenger RNA (mRNA) by retrotranscription followed by real-time polymerase chain reaction as a diagnostic test in samples obtained from bone marrow, peripheral blood, and cerebrospinal fluid (CSF) at diagnosis, after induction chemotherapy, and during follow-up. The study was conducted from June 30, 2008, to June 30, 2014. Seventeen retinoblastoma primary tumors, 2 retinoblastoma cell lines, and 47 samples of bone marrow from other cancers (controls) were studied. Seventeen patients with metastatic retinoblastoma (9 at diagnosis, 8 at relapse; age range: 18-41 months) were included.

MAIN OUTCOMES AND MEASURES:

Detection of CRX mRNA as a marker for metastatic retinoblastoma and MD in bone marrow and CSF and its correlation with clinical findings.

RESULTS:

Cone-rod homeobox mRNA was expressed in all tumors (relative expression levels range, 8.1 × 10-5 to 5.6) and cell lines. In control samples, there was no amplification of CRX; only the housekeeping gene (GAPDH) demonstrated amplification. Bone marrow metastatic cells showed expression of CRX mRNA in all 9 children presenting with metastasis at the diagnosis (relative expression levels, 6.0 × 10-5 to 0.67). After induction chemotherapy, no evidence of MD of tumor cells was seen in any of the 8 responding children since only GAPDH showed amplification. In the CSF of children who had a metastatic relapse, CRX mRNA detection was positive in 2 patients in whom no conclusive results were reached by immunocytology for disialoganglioside GD2. Minimal dissemination in the CSF was associated with a clinical relapse in 2 cases. No concomitant MD was evident in the bone marrow in any case.

CONCLUSIONS AND RELEVANCE:

These data suggest that CRX mRNA is a novel marker for retinoblastoma at extraocular sites. In this study among patients with bone marrow metastasis, there was a quick, complete, and sustained molecular response after induction chemotherapy. In all patients with secondary metastasis, CSF relapse occurred independently from the bone marrow, suggesting a sanctuary site.

• Authors: Ana V Torbidoni, Viviana E Laurent, Claudia Sampor, Daniela Ottaviani, Valeria Vazquez, Mariano R Gabri, Jorge Rossi, María T de Dávila, Cristina Alonso, Daniel F Alonso, Guillermo L Chantada
• Journal: JAMA ophthalmology (JAMA Ophthalmol) Vol. 133 Issue 7 Pg. 805-12 (Jul 2015) ISSN: 2168-6173 [Electronic] United States
• PMID: 25928893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Homeodomain Proteins
• RNA, Messenger
• Trans-Activators
• Transcription Factors
• cone rod homeobox protein

Topics

• Child, Preschool
• Cohort Studies
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease (epidemiology)
• Homeodomain Proteins (genetics)
• Humans
• Incidence
• Infant
• Male
• Neoplasm Invasiveness (pathology)
• Neoplasm Metastasis
• Neoplasm Staging
• Prospective Studies
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction (methods)
• Retinal Neoplasms (epidemiology, genetics, pathology)
• Retinoblastoma (epidemiology, genetics, secondary)
• Risk Assessment
• Sensitivity and Specificity
• Survival Analysis
• Trans-Activators (genetics)
• Transcription Factors (genetics)