Retinoma and retinoblastoma: Genomic hybridisation

Abstract

Retinoblastoma research has been fundamental in uncovering the role of tumor suppressor genes in human cancer and lead to Alfred Knudson’s “two hits” model. However, cytogenetic and comparative genomic hybridization studies in retinoblastoma have shown that, in addition to RB1 mutations (M1-M2 events), other recurrent genomic aberrations (M3-Mn events) are present: gains on 6p, 1q and 2p and losses of 16q. In this scenario, the benign lesion called “retinoma” represents a very interesting tissue to investigate the timing of genomic instability in retinoblastoma. We employed array-CGH methodology at high-resolution (25 kb) to analyse 18 eye samples, 10 from bilateral and 8 from unilateral retinoblastoma patients. Interestingly, two unilateral cases also showed areas of retinoma. The highly frequent rearrangements involved chromosomes 1, 2, 6, 9, 11 and 13. In particular, the entire p arm of chromosome 6 was duplicated in 40% of cases. Results also demonstrated that bilateral cases show a lower number of rearrangements respect to unilateral cases, with statistical significance (p = 0.002). As concerns the group of unilateral cases, it can be divided into low and high-level chromosomal instability groups (respectively ≤4 and ≥7 rearrangements), the first presenting with younger age at diagnosis. In one retinoma, ophthalmoscopically diagnosed, array-CGH did not reveal any genomic aberration. In the other case of retinoma, identified by retrospective histopatological examination, array-CGH revealed the presence of five genomic imbalances. Two gene-free rearrangements were retinoma specific; three were in common with adjacent retinoblastoma. One rearrangement (dup5p) was present only in retinoblastoma and included SKP2 as interesting candidate gene for retinoma-retinoblastoma transition. Array-CGH therefore demonstrated that the two retinomas are indeed different molecular entities: the first is a pretumoral lesion while the second one represents a subclone of cells adjacent to another subclone bearing a set of rearrangements with more selective growth advantage.