Array comparative genomic hybridization in retinoma and retinoblastoma tissues

Abstract

In retinoblastoma, two RB1 mutations are necessary for tumor development. Recurrent genomic rearrangements may represent subsequent events required for retinoblastoma progression. Array-comparative genomic hybridization was carried out in 18 eye samples, 10 from bilateral and eight from unilateral retinoblastoma patients. Two unilateral cases also showed areas of retinoma. The most frequent imbalance in retinoblastomas was 6p gain (40%), followed by gains at 1q12-q25.3, 2p24.3-p24.2, 9q22.2, and 9q33.1 and losses at 11q24.3, 13q13.2-q22.3, and 16q12.1-q21. Bilateral cases showed a lower number of imbalances than unilateral cases (P = 0.002). Unilateral cases were divided into low-level (£4) and high-level (³7) chromosomal instability groups. The first group presented with younger age at diagnosis (mean 511 days) compared with the second group (mean 1606 days). In one retinoma case ophthalmoscopically diagnosed as a benign lesion no rearrangements were detected, whereas the adjacent retinoblastoma displayed seven aberrations. The other retinoma case identified by retrospective histopathological examination shared three rearrangements with the adjacent retinoblastoma. Two other gene-free rearrangements were retinoma specific. One rearrangement, dup5p, was retinoblastoma specific and included the SKP2 gene. Genomic profiling indicated that the first retinoma was a pretumoral lesion, whereas the other represents a subclone of cells bearing 'benign' rearrangements overwhelmed by another subclone presenting aberrations with higher 'oncogenic' potential. In summary, the present study shows that bilateral and unilateral retinoblastoma have different chromosomal instability that correlates with the age of tumor onset in unilateral cases. This is the first report of genomic profiling in retinoma tissue, shedding light on the different nature of lesions named 'retinoma'. (Cancer Sci 2009; 100: 465-471) R etinoblastoma (RB, OMIM#180200) is the most common primary intraocular malignancy in children, initiated by the inactivation of both alleles of the RB1 tumor-suppressor gene. (1,2) Approximately 40% of RB patients carry a predisposing germline mutation transmitted as an autosomal-dominant trait. In these patients, inactivation of the second RB1 allele occurs in the retinal cells and generally results in multiple and often bilateral tumors. In the remaining 60% of children, both mutational events occur in the same retinal cell leading to unilateral sporadic RB. Retinoma (RN), a benign retinal lesion, is considered to be the precursor of RB.(4,5) Unlike RB, which is typically opaque white, RN appears as a translucent gray retinal mass, frequently associated with calcification and retinal pigment epithelial hyperplasia. (6) The histopathology of RN includes foci of photoreceptor differentiation (fleurettes), momomorphic round nuclei, abundant fibrillar eosinophilic stroma, and absence of mitotic activity.Recently, it has been demonstrated that the two mutational events inactivating the RB1 gene are already present in RN.(4) U...

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