In addition to RB1 gene mutations, retinoblastomas frequently show gains of 1q and 6p and losses of 16q. To identify suppressor genes on 16q, we analyzed 22 short tandem repeat loci in 58 patients with known RB1 mutations. A subset of tumors was also investigated by conventional and matrix comparative genomic hybridization. In 40 of 58 (69%) tumors, we found no loss of heterozygosity (LOH) at any 16q marker. LOH was detected in 18 of 58 (31%) tumors, including five with allelic imbalance at some markers. In one tumor LOH was only observed at 16q24. As the parental origin of allele loss was unbiased, an imprinted locus is unlikely to be involved. Analysis of gene expression by microarray hybridization and quantitative RT real-time PCR did not identify a candidate suppressor in 16q24. Cadherin 13 (CDH13), CBFA2T3, and WFDC1, which are candidate suppressors in other tumor entities with 16q24 loss, did not show loss of expression. In addition, mutation and methylation analysis showed no somatic alteration of CDH13. Results in all tumors with chromosome 16 alterations define a single minimal deleted region of 5.7 Mb in the telomeric part of 16q24 with the centromeric boundary defined by retention of heterozygosity for a single nucleotide variant in exon 10 of CDH13 (Mb 82.7). Interestingly, clinical presentation of tumors with and without 16q alterations was distinct. Specifically, almost all retinoblastomas with 16q24 loss showed diffuse intraocular seeding. This suggests that genetic alterations in the minimal deleted region are associated with impaired cell-to-cell adhesion.
Our findings suggest a role for neurotrophin signaling in the biology of retinoblastoma. General Trk inhibitors are effective in decreasing growth rates of retinoblastoma cells in vitro, and should be evaluated in in vivo studies.
Plasmin is the key enzyme of fibrinolysis. Plasmin-alpha2-antiplasmin (PAP) complexes are biomarkers of fibrinolysis activation. The purpose of our investigation was to evaluate the activity of fibrinolysis in normal human eyes, that is in eyes without blood-retina barrier breakdown (BRB), which has not been investigated so far. Twenty-two vitreal samples were harvested at the beginning of a standard 23-gauge three-port pars plana vitrectomy for macular pucker removal, macular hole closure or vitreal floater removal from the central vitreous body. These samples were immediately stabilized with human albumin (2.5% final conc.) and arginine (1.25 mmol/l final conc.) and subsequently frozen. Plasminogen was functionally determined in an ultra-sensitive pNA reaction after activation with streptokinase (100% = functional plasminogen in pooled normal citrated plasma). PAP concentrations were measured by enzyme immune assay (EIA). Intravitreal functional plasminogen exhibited to be 1 ± 0.65% (range: 0.2-2.49%). PAP concentrations ranged at levels of 14 ± 9ng/ml (range: 2-33 ng/ml). Pearson's correlation quotient between functional plasminogen and PAP revealed to be r equal to -0.27 (P = 0.221). No adverse events or serious side effects occurred. Sampling vitreous fluid at the beginning of a standard 23-gauge three-port pars plana vitrectomy is a well tolerated procedure. A strict stabilization procedure for extracted vitreous specimen is necessary to obtain activities and concentrations that are close to the true intraocular value. There is a basal intraocular fibrinolysis, a possible target for intravitreal pharmacological therapy.
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