Marked differences in unilateral isolated retinoblastomas from young and older children studied by comparative genomic hybridization

Although it is established that the loss of function of both alleles of the RB1 gene is a prerequisite for the development of retinoblastoma, little i s known about the genetic events that are required for tumor progression. W e used comparative genomic hybridization (CGH) to search for DNA copy numbe r changes in isolated unilateral retinoblastomas. From a series of 66 patie nts with retinoblastomas with somatic mutations in both RBI alleles, tumor samples from 13 children with the youngest (2.0-9.8 months) and 13 with the oldest (36.2-84.1 months) age at operation were studied. Loss at 13q14, th e location of RBI, was demonstrated in two tumors only. Recurring chromosom e imbalances included gains at 6p (11/26), 1q(10/26), 2p (4/26), and 17q (4 /26), gains of the entire chromosome 19 (3/26), and losses at 16q (9/26). A commonly gained region at 1q32 was identified. Increased dosage of GAC1, a candidate oncogene located in 1q32, was found in two of four tumors by Sou thern blot analysis. Comparison of the CGH findings revealed that retinobla stomas from children with an older age at operation showed significantly mo re frequent (13/13 cases vs 4/13 cases; P=0.0005) and more complex genetic abnormalities (median, 5 changes/abnormal tumor vs median, 1.5 changes/abno rmal tumor; P=0.003) than retinoblastomas from children with a young age at operation. Gains at Iq, 2p, 17q, of the entire chromosome 19 and losses of 16q were restricted to the older age group. Our results suggest that the p rogression of retinoblastomas from older patients follows mutational pathwa ys different from those of younger patients.